The present invention is directed to certain novel compounds represented by structural Formula (I) 
or pharmaceutically acceptable salt forms thereof, wherein R1, R6a, R6b, R7, R8, R9, X, b, m, and n are described herein. The invention is also concerned with pharmaceutical formulations comprising these novel compounds as active ingredients and the use of the novel compounds and their formulations in the treatment of certain disorders. The compounds of this invention are serotonin agonists and antagonists and are useful in the control or prevention of central nervous system disorders including obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility.
There exists a substantial correlation for the relationship between 5-HT2 receptor modulation and a variety of diseases and therapies. To date, three subtypes of the 5-HT2 receptor class have been identified, 5-HT2A, 5-HT2B, and 5-HT2C. Prior to the early 1990""s the 5-HT2C and 5-HT2A receptors were referred to as 5-HT1C and 5-HT2, respectively.
The agonism or antagonism of 5-HT2 receptors, either selectively or nonselectively, has been associated with the treatment of various central nervous system (CNS) disorders Ligands possessing affinity for the 5-HT2 receptors have been shown to have numerous physiological and behavioral effects (Trends in Pharmacological Sciences, 11, 181, 1990). In the recent past the contribution of serotonergic activity to the mode of action of antidepressant drugs has been well documented. Compounds that increase the overall basal tone of serotonin in the CNS have been successfully developed as antidepressants. The serotonin selective reuptake inhibitors (SSRI) function by increasing the amount of serotonin present in the nerve synapse. These breakthrough treatments, however, are not without side effects and suffer from delayed onset of action (Leonard, J. Clin. Psychiatry, 54(suppl), 3, 1993). Due to the mechanism of action of the SSRIs, they effect the activity of a number of serotonin receptor subtypes. This non-specific modulation of the serotonin family of receptors most likely plays a significant role in the side effect profile. In addition, these compounds often have a high affinity for a number of the serotonin receptors as well as a multitude of other monoamine neurotransmitters and nuisance receptors. Removing some of the receptor cross reactivity would allow for the examination and possible development of potent therapeutic ligands with an improved side effect profile.
There is ample evidence to support the role of selective 5-HT2 receptor ligands in a number of disease therapies. Modulation of 5-HT2 receptors has been associated with the treatment of schizophrenia and psychoses (Ugedo, L., et. al., Psychopharmacology, 98, 45, 1989). Mood, behavior and hallucinogenesis can be affected by 5-HT2 receptors in the limbic system and cerebral cortex. 5-HT2 receptor modulation in the hypothalamus can influence appetite, thermoregulation, sleep, sexual behavior, motor activity, and neuroendocrine function (Hartig, P., et. al., Annals New York Academy of Science, 149, 159). There is also evidence indicating that 5-HT2 receptors mediate hypoactivity, effect feeding in rats, and mediate penile erections (Pyschopharmacology, 101, 57, 1990).
Compounds exhibiting selectivity for the 5-HT2B receptor are useful in treating conditions such as tachygastria, hypermotility associated with irritable bowel disorder, constipation, dyspepsia, and other peripherally mediated conditions.
5-HT2A antagonists have been shown to be effective in the treatment of schizophrenia, anxiety, depression, and migraines (Koek, W., Neuroscience and Behavioral reviews, 16, 95, 1996). Aside from the beneficial antipsychotic effects, classical neuroleptic are frequently responsible for eliciting acute extrapyramidal side effects and neuroendocrine disturbances. These compounds generally possess signifcant dopamine D2 receptor affinity (as well as other nuisance receptor affinity) which frequently is associated with extra pyramidal symptoms and tardive dyskinesia, thus detracting from their efficacy as front line treatments in schizophrenia and related disorders. Compounds possessing a more favorable selectivity profile would represent a possible improvement for the treatment of CNS disorders.
U.S. Pat. Nos. 3,914,421; 4,013,652; 4,115,577; 4,183,936; and 4,238,607 disclose pyridopyrrolobenz-heterocycles of formula: 
where X is O, S, S(xe2x95x90O), or SO2; n is 0 or 1; R1 is various carbon substituents, and Z is a monosubstituent of H, methyl, or chloro.
U.S. Pat. No. 4,219,550 discloses pyridopyrrolo-benzheterocycles of formula: 
where X is O or S; R1 is C1-4 alkyl or cyclopropyl; R2 is H, CH3, OCH3, Cl, Br, F, or CF3; and (A) is xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, or xe2x80x94CH2CH2xe2x80x94.
European Patent Application EP 473,550 A1 discloses indolonaphthyridines of formula: 
wherein X and Y are H or a simple ring, R1, is H, alkyl, alkylcarbonylalkyl, arylcarbonylalkyl, aralkyl, or a mono or disubstituted carbamoylalkyl; and R3, R4, and R5 are H, halogen, alkyl, alkoxy, alkylthio or trifluoromethyl.
None of the above references suggest or disclose the compounds of the present invention.
There remains a need to discover new compounds useful as serotonin agonists and antagonists which are useful in the control or prevention of central nervous system disorders. As such, the present invention discloses novel compounds which are of low molecular weight, useful as serotonin agonists and antagonists, and provide good in vitro potency.
One object of the present invention is to provide novel compounds which are useful as agonists or antagonists of 5-HT2 receptors, more specifically 5-HT2A and 5-HT2C receptors, or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating central nervous system disorders including obesity, anxiety, depression, psychosis, schizophrenia, sleep and sexual disorders, migraine and other conditions associated with cephalic pain, social phobias, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof. More specifically, the present invention provides a method for treating obesity anxiety, depression, or schizophrenia.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors, discovery that compounds of Formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein R1, R6a, R6b, R7, R8, R9, X, b, m, and n are defined below, are effective agonists or antagonists of 5-HT2 receptors.
Thus, in a first embodiment, the present invention provides a novel compound of Formula (I): 
or a stereoisomer or a pharmaceutically acceptable salt form thereof, wherein:
b is a single bond wherein the bridging hydrogens are either cis or trans;
X is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, NR10xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94S(xe2x95x90O)CH2xe2x80x94, xe2x80x94S(xe2x95x90O)2CH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94CH2S(xe2x95x90O)xe2x80x94, xe2x80x94CH2S(xe2x95x90O)2xe2x80x94, xe2x80x94NR10CH2xe2x80x94, xe2x80x94CH2NR10xe2x80x94, xe2x80x94NHC(xe2x95x90O)xe2x80x94, or xe2x80x94C(xe2x95x90O)NHxe2x80x94;
R1 is selected from
H,
C(xe2x95x90O)R2,
C(xe2x95x90O) OR2,
C1-8 alkyl,
C2-8 alkenyl,
C2-8 alkynyl,
C3-7 cycloalkyl,
C1-6 alkyl substituted with Z,
C2-6 alkenyl substituted with Z,
C2-6 alkynyl substituted with Z,
C3-6 cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;
C1-3 alkyl substituted with Y,
C2-3 alkenyl substituted with Y,
C2-3 alkynyl substituted with Y,
C1-6 alkyl substituted with 0-2 R2,
C2-6 alkenyl substituted with 0-2 R2,
C2-6 alkynyl substituted with 0-2 R2,
aryl substituted with 0-2 R2, and
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with 0-2 R2;
Y is selected from
C3-6 cycloalkyl substituted with Z, aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclicring system substituted with Z;
C3-6 cycloalkyl substituted with xe2x80x94(C1-3 alkyl)xe2x80x94Z,
aryl substituted with xe2x80x94(C1-3 alkyl)xe2x80x94Z, and
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with xe2x80x94(C1-3 alkyl)xe2x80x94Z;
Z is selected from H,
xe2x80x94CH(OH)R2,
xe2x80x94C(ethylenedioxy)R2,
xe2x80x94OR2,
SR2,
xe2x80x94NR2R3,
xe2x80x94C(O)R2,
xe2x80x94C(O)NR2R3,
xe2x80x94NR3C(O)R2,
xe2x80x94C(O) OR2,
xe2x80x94OC(O)R2,
xe2x80x94CH(xe2x95x90NR4)NR2R3,
xe2x80x94NHC(xe2x95x90NR4)NR2R3,
xe2x80x94S(O)R2,
xe2x80x94S(O)2R2,
S(O)2NR2R3, and xe2x80x94NR3S(O)2R2;
R2, at each occurrence, is independently selected from
halo,
C1-3 haloalkyl,
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
aryl substituted with 0-5 R42;
C3-10 carbocyclic residue substituted with 0-3 R41, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R3, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 alkoxy;
alternatively, R2 and R3 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94or xe2x80x94N(R4)xe2x80x94;
R4, at each occurrence, is independently selected from H and C1-4 alkyl;
R6a is H or C1-4 alkyl;
R6b is H;
alternatively, R6a and R6b are taken together to form xe2x95x90O or xe2x95x90S;
R7 and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13,
NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12,
CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12,
S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12,
NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and
NR12C(O)NHR15;
R8 is selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C2-4 alkenyl substituted with 0-2 R11,
C2-4 alkynyl substituted with 0-1 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13,
NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12,
CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12,
S(O)NR12R13, S(O)2, NR12R13, NR14S(O)R12, NR14S(O)2R12,
NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and
NR12C(O) NHR15;
R10 is selected from H,
C1-4 alkyl substituted with 0-2 R10A,
C2-4 alkenyl substituted with 0-2 R10A,
C2-4 alkynyl substituted with 0-1 R10A, and
C1-4 alkoxy;
R10A is selected from
C1-4 alkoxy,
C3-6 carbocyclic residue substituted with 0-3 R33,
phenyl substituted with 0-3 R33, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S; substituted with 0-2 R44;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, C3-10 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13,
NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12,
CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12,
S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12,
NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and
NR12C(O)NHR15;
R12, at each occurrence, is independently selected from
C1-4 alkyl substituted with 0-1 R12a,
C2-4 alkenyl substituted with 0-1 R12a,
C2-4 alkynyl substituted with 0-1 R12a,
C3-6 cycloalkyl substituted with 0-3 R33,
aryl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12a, at each occurrence, is independently selected from phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R14)xe2x80x94;
alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein said bicyclic heterocyclic ring system is unsaturated or partially saturated, wherein said bicyclic heterocyclic ring system is substituted with 0-3 R16;
R14, at each occurrence, is independently selected from H and C1-4 alkyl;
R15, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
R16, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-3 haloalkyl-oxy-, C1-3 alkyloxy-, and xe2x95x90O;
R31, at each occurrence, is independently selected from
H, OH, halo, CF3, SO2R45, NR46R47, C1-4 alkyl, and xe2x95x90O;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H, xe2x95x90O, phenyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(xe2x95x90O)xe2x80x94, C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94, C1-4 alkyl-OC(xe2x95x90O)xe2x80x94, C1-4 alkyl-C(xe2x95x90O)Oxe2x80x94, C3-6 cycloalkyl-oxy-, C3-6 cycloalkylmethyl-oxy-;
C1-6 alkyl substituted with OH, methoxy, ethoxy, propoxy, butoxy, xe2x80x94SO2R45, xe2x80x94NR46R47, NR46R47C(xe2x95x90O)xe2x80x94, or (C1-4 alkyl)CO2xe2x80x94; and
C2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, butoxy, xe2x80x94SO2R45, xe2x80x94NR46R47, NR46R47C(xe2x95x90O)xe2x80x94, or (C1-4 alkyl)CO2xe2x80x94;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, xe2x95x90O;
C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R42, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, SOR45, SR45, NR46SO2R45, NR46COR45, NR46R47, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH) NH2,
C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R44, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R43 is C3-6 cycloalkyl or aryl substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H, halo, xe2x80x94OH, NR46R47, CO2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2, C1-4 alkyl, and C1-4 alkoxy;
R45 is C1-4 alkyl;
R46, at each occurrence, is independently selected from H and C1-4 alkyl;
R47, at each occurrence, is independently selected from H, C1-4 alkyl, xe2x80x94C(xe2x95x90O)NH(C1-4 alkyl), xe2x80x94SO2(C1-4 alkyl), xe2x80x94C(xe2x95x90O)O(C1-4 alkyl), xe2x80x94C(xe2x95x90O)(C1-4 alkyl), and xe2x80x94C(xe2x95x90O)H;
n is 1 or 2;
m is 1 or 2; and
n plus m is 2, 3, or 4;
provided when n is 1, m is 2, and R7, R8, and R9 are independently selected from H, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio or trifluoromethyl; then X is not a bond.
[2] In an another embodiment, the present invention provides a novel compound of Formula (I) wherein:
X is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94NR10CH2xe2x80x94, or xe2x80x94CH2NR10xe2x80x94;
R1 is selected from
H,
C(xe2x95x90O)R2,
C(xe2x95x90O)OR2,
C1-8 alkyl,
C2-8 alkenyl,
C2-8 alkynyl,
C3-7 cycloalkyl,
C1-6 alkyl substituted with 0-2 R2,
C2-6 alkenyl substituted with 0-2 R2,
C2-6 alkynyl substituted with 0-2 R2,
aryl substituted with 0-2 R2, and
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with 0-2 R2;
R2, at each occurrence, is independently selected from
F, Cl, CH2F, CHF2, CF3,
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
phenyl substituted with 0-5 R42;
C3-10 carbocyclic residue substituted with 0-3 R41, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R6a is H or C1-4 alkyl;
R6b is H;
alternatively, R6a and R6b are taken together to form xe2x95x90O or xe2x95x90S;
R7 and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O))NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O) NHR15;
R8 is selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C2-4 alkenyl substituted with 0-2 R11,
C2-4 alkynyl substituted with 0-1 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O), 2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O) NHR15;
R10 is selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 alkoxy;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, C3-10 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O) NHR15;
R12, at each occurrence, is independently selected from
C1-4 alkyl substituted with 0-1 R12a,
C2C4 alkenyl substituted with 0-1 R12a,
C2-4 alkynyl substituted with 0-1 R12a,
C3-6 cycloalkyl substituted with 0-3 R33,
aryl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12a, at each occurrence, is independently selected from
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94or xe2x80x94N(R14)xe2x80x94;
alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein said bicyclic heterocyclic ring system is unsaturated or partially saturated, wherein said bicyclic heterocyclic ring system is substituted with 0-3 R16;
R14, at each occurrence, is independently selected from H and C1-4 alkyl;
R15, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
R16, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl,
C1-3 haloalkyl-oxy-, C1-3 alkyloxy-, and xe2x95x90O;
R31, at each occurrence, is independently selected from
H, OH, halo, CF3, SO2R45, NR46R47, C1-4 alkyl, and xe2x95x90O;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
xe2x95x90O, phenyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-,
C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(xe2x95x90O)xe2x80x94,
C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94, C1-4 alkyl-OC(xe2x95x90O)xe2x80x94,
C1-4 alkyl-C(xe2x95x90O)Oxe2x80x94, C3-6 cycloalkyl-oxy-,
C3-6 cycloalkylmethyl-oxy-;
C1-6 alkyl substituted with OH, methoxy, ethoxy, propoxy, butoxy, xe2x80x94SO2R45, xe2x80x94NR46R47, NR46R47C(xe2x95x90O)xe2x80x94, or (C1-4 alkyl)CO2xe2x80x94; and
C2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, butoxy, xe2x80x94SO2R45, xe2x80x94NR46R47, NR46R47C(xe2x95x90O)xe2x80x94, or (C1-4 alkyl)CO2xe2x80x94;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN;
C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R42, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R44, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R43 is C3-6 cycloalkyl or aryl substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H, halo, xe2x80x94OH, NR46R47, CO2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2, C1-4 alkyl, and C1-4 alkoxy;
R45 is C1-4 alkyl;
R46, at each occurrence, is independently selected from H and C1-4 alkyl;
R47, at each occurrence, is independently selected from H and C1-4 alkyl;
n is 1 or 2;
m is 1 or 2; and
n plus m is 2, 3, or 4;
provided when n is 1, m is 2, and R7, R8, and R9 are independently selected from H, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio or trifluoromethyl; then X is not a bond.
[3] In an another embodiment, the present invention provides a novel compound of Formula (I) wherein:
X is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, or xe2x80x94CH2Sxe2x80x94;
R1 is selected from
H,
C(xe2x95x90O)R2,
C(xe2x95x90O) OR2,
C1-6 alkyl,
C2-6 alkenyl,
C2-6 alkynyl,
C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-2 R2,
C2-4 alkenyl substituted with 0-2 R2, and
C2-4 alkynyl substituted with 0-2 R2;
R2, at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
phenyl substituted with 0-5 R42;
C3-10 carbocyclic residue substituted with 0-3 R41, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R6a is H or C1-4 alkyl;
R6b is H;
alternatively, R6a and R6b are taken together to form xe2x95x90O or xe2x95x90S;
R7 and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, and NR14S(O)2R12;
R8 is selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C2-4 alkenyl substituted with 0-2 R11,
C2-4 alkynyl substituted with 0-1 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2, C1-6 alkyl,
C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C3-10 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, and NR14S(O)2R12;
R12, at each occurrence, is independently selected from
C1-4 alkyl substituted with 0-1 R12a,
C2-4 alkenyl substituted with 0-1 R12a,
C2-4 alkynyl substituted with 0-1 R12a,
C3-6 cycloalkyl substituted with 0-3 R33,
aryl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12a, at each occurrence, is independently selected from
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R14)xe2x80x94;
alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein said bicyclic heterocyclic ring system is unsaturated or partially saturated, wherein said bicyclic heterocyclic ring system is substituted with 0-3 R16;
R14, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R15, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
R16, at each occurrence, is independently selected from H, OH, F, Cl, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, and xe2x95x90O;
R31, at each occurrence, is independently selected from H, OH, halo, CF3, SO2R45, NR46R47, C1-4 alkyl, and xe2x95x90O;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
xe2x95x90O, phenyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-,
C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(xe2x95x90O)xe2x80x94,
C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94, C1-4 alkyl-OC(xe2x95x90O)xe2x80x94,
C1-4 alkyl-C(xe2x95x90O)Oxe2x80x94, C3-6 cycloalkyl-oxy-,
C3-6 cycloalkylmethyl-oxy-;
C1-6 alkyl substituted with OH, methoxy, ethoxy, propoxy, butoxy, xe2x80x94SO2R45, xe2x80x94NR46R47, NR46R47C(xe2x95x90O)xe2x80x94, or (C1-4 alkyl)CO2xe2x80x94; and
C2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, butoxy, xe2x80x94SO2R45, xe2x80x94NR46R47, NR46R47C(xe2x95x90O)xe2x80x94, or (C1-4 alkyl)CO2xe2x80x94;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN,
C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R42, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH) NH2,
C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R44, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R43 is C3-6 cycloalkyl or aryl substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H, halo, xe2x80x94OH, NR46R47, CO2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2, C1-4 alkyl, and C1-4 alkoxy;
R45 is C1-4 alkyl;
R46, at each occurrence, is independently selected from H and C1-4 alkyl;
R47, at each occurrence, is independently selected from H and C1-4 alkyl;
n is 1 or 2;
m is 1 or 2; and
n plus m is 2, 3, or 4;
provided when n is 1, m is 2, and R7, R8, and R9 are independently selected from H, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio or trifluoromethyl; then X is not a bond.
[4] In an another embodiment, the present invention provides a novel compound of Formula (I) wherein:
X is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94OCH2xe2x80x94, or xe2x80x94SCH2xe2x80x94;
R1 is selected from
H,
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-4 cycloalkyl,
C1-3 alkyl substituted with 0-1 R2,
C2-3 alkenyl substituted with 0-1 R2, and
C2-3 alkynyl substituted with 0-1 R2;
R2, at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
phenyl substituted with 0-5 R42;
C3-6 carbocyclic residue substituted with 0-3 R41, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R6a is H, methyl, ethyl, propyl, or butyl;
R6b is H;
alternatively, R6a and R6b are taken together to form xe2x95x90O or xe2x95x90S;
R7 and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R8 is selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C2-4 alkenyl substituted with 0-2 R11,
C2-4 alkynyl substituted with 0-1 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, NR12C(O)NHR15, NR14C(O)R12, NR14C(O) OR12, and NR14S(O)2R12;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12, at each occurrence, is independently selected from
C1-4 alkyl substituted with 0-1 R12a,
C2-4 alkenyl substituted with 0-1 R12a,
C2-4 alkynyl substituted with 0-1 R12a,
C3-6 cycloalkyl substituted with 0-3 R33,
aryl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12a, at each occurrence, is independently selected from
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94or xe2x80x94N(R14)xe2x80x94;
alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1-3 heteroatoms selected from the group consisting of one N, two N, three N, one N one O, and one N one S; wherein said bicyclic heterocyclic ring system is unsaturated or partially saturated, wherein said bicyclic heterocyclic ring system is substituted with 0-2 R16;
R14, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R16, at each occurrence, is independently selected from H, OH, F, Cl, CN, NO2, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy;
R31, at each occurrence, is independently selected from H, OH, halo, CF3, methyl, ethyl, and propyl;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
phenyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-,
C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(xe2x95x90O)xe2x80x94,
C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94, C1-4 alkyl-OC(xe2x95x90O)xe2x80x94,
C1-4 alkyl-C(xe2x95x90O)Oxe2x80x94, C3-6 cycloalkyl-oxy-,
C3-6 cycloalkylmethyl-oxy-;
C1-6 alkyl substituted with OH, methoxy, ethoxy, propoxy, butoxy, xe2x80x94SO2R45, xe2x80x94NR46R47, NR46R47C(xe2x95x90O)xe2x80x94, or (C1-4 alkyl)CO2xe2x80x94; and
C2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, butoxy, xe2x80x94SO2R45, xe2x80x94NR46R47, NR46R47C(xe2x95x90O)xe2x80x94, or (C1-4 alkyl)CO2xe2x80x94;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN,
C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 alkyl;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, C3-6 cycloalkyl, and C1-3 alkyl;
R43 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl, each substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H, halo, xe2x80x94OH, NR46R47, CO2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;
R45 is methyl, ethyl, propyl, or butyl;
R46, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R47, at each occurrence, is independently selected from from H, methyl, ethyl, propyl, and butyl;
n is 1 or 2;
m is 1 or 2; and
n plus m is 2 or 3;
provided when n is 1, m is 2, and R7, R8, and R9 are independently selected from H, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio or trifluoromethyl; then X is not a bond.
[5] In an another embodiment, the present invention provides a novel compound of Formula (I) wherein:
X is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94OCH2xe2x80x94, or xe2x80x94SCH2xe2x80x94;
R1 is selected from
H,
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-4 cycloalkyl,
C1-3 alkyl substituted with 0-1 R2,
C2-3 alkenyl substituted with 0-1 R2, and
C2-3 alkynyl substituted with 0-1 R2;
R2, at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
phenyl substituted with 0-5 R42;
C3-6 carbocyclic residue substituted with 0-3 R41, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R6a is H;
R6b is H;
alternatively, R6a and R6b are taken together to form xe2x95x90O;
R7 and R9, at each occurrence, are independently selected from
H, F, Cl, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, and xe2x80x94NO2,
R8 is selected from
H, F, Cl, Br, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C2-4 alkenyl substituted with 0-2 R11,
C2-4 alkynyl substituted with 0-1 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, NR12C(O)R15, NR12C(O) OR15, NR12S(O)2R15, NR12C(O)NHR15, NR14C(O)R12, NR14C(O)OR12, and NR14S(O)2R12;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12, at each occurrence, is independently selected from
C1-4 alkyl substituted with 0-1 R12a,
C2-4 alkenyl substituted with 0-1 R12a,
C2-4 alkynyl substituted with 0-1 R12a,
C3-6 cycloalkyl substituted with 0-3 R33,
aryl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12a, at each occurrence, is independently selected from
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R14)xe2x80x94;
alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S; wherein said bicyclic heterocyclic ring system is selected from indolyl, indolinyl, indazolyl, benzimidazolyl, benzimidazolinyl, benztriazolyl, is quinolinyl, tetrahydroquinolinyl, isoquinolinyl, and tetrahydroisoquinolinyl; wherein said bicyclic heterocyclic ring system is substituted with 0-1 R16;
R14, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R16, at each occurrence, is independently selected from
H, OH, F, Cl, CN, NO2, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy;
R31, at each occurrence, is independently selected from
H, OH, halo, CF3, methyl, ethyl, and propyl;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
phenyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-,
C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(xe2x95x90O)xe2x80x94, C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94, C1-4 alkyl-OC(xe2x95x90O)xe2x80x94,
C1-4 alkyl-C(xe2x95x90O)Oxe2x80x94, C3-6 cycloalkyl-oxy-,
C3-6 cycloalkylmethyl-oxy-;
C1-6 alkyl substituted with OH, methoxy, ethoxy, propoxy, butoxy, xe2x80x94SO2R45, xe2x80x94NR46R47, NR46R47C(xe2x95x90O)xe2x80x94, or (C1-4 alkyl)CO2xe2x80x94; and
C2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, butoxy, xe2x80x94SO2R45, xe2x80x94NR46R47, NR46R47C(xe2x95x90O)xe2x80x94, or (C1-4 alkyl)CO2xe2x80x94;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN,
C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 alkyl;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, C3-6 cycloalkyl, and C1-3 alkyl;
R43 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl, each substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H, halo, xe2x80x94OH, NR46R47, CO2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;
R45 is methyl, ethyl, propyl, or butyl;
R46, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R47, at each occurrence, is independently selected from from H, methyl, ethyl, propyl, and butyl;
n is 1; and
m is 1.
[6] In an another embodiment, the present invention provides a novel compound of Formula (I) wherein:
X is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94OCH2xe2x80x94, or xe2x80x94SCH2xe2x80x94;
R1 is selected from H,
C1-5 alkyl substituted with 0-1 R2,
C2-5 alkenyl substituted with 0-1 R2, and
C2-3 alkynyl substituted with 0-1 R2;
R2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl;
R6a is H;
R6b is H;
R7 and R9, at each occurrence, are independently selected from H, F, Cl, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, and xe2x80x94NO2;
R8 is selected from R11;
methyl substituted with R11;
phenyl substituted with 0-3 R33;
pyridyl substituted with 0-2 R33;
OR12, SR12, NR12R13, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, NR12C(O)NHR15, NR14C(O)R12, NR14C(O)oRL2, and NR14S(O)2R12;
R11 is selected from
phenyl-substituted with 0-5 fluoro;
pyridyl substituted with 0-2 R33;
naphthyl-substituted with 0-2 R33;
2-(H3CCH2C(xe2x95x90O))-phenyl-substituted with R33;
2-(H3CC(xe2x95x90O))-phenyl-substituted with R33;
2-(HC(xe2x95x90O))-phenyl-substituted with R33;
2-(H3CCH(OH))-phenyl-substituted with R33;
2-(H3CCH2CH(OH))-phenyl-substituted with R33;
2-(HOCH2)-phenyl-substituted with R33;
2-(HOCH2CH2)-phenyl-substituted with R33;
2-(H3COCH2)-phenyl-substituted with R33;
2-(H3COCH2CH2)-phenyl-substituted with R33;
2-(H3CCH(OMe))-phenyl-substituted with R33;
2-(H3COC(xe2x95x90O))-phenyl-substituted with R33;
2-(HOCH2CHxe2x95x90CH)-phenyl-substituted with R33;
2-((MeOCxe2x95x90O)CHxe2x95x90CH)-phenyl-substituted with R33;
2-(methyl)-phenyl-substituted with R33;
2-(ethyl)-phenyl-substituted with R33;
2-(i-propyl)-phenyl-substituted with R33;
2-(F3C)-phenyl-substituted with R33;
2-(NC)-phenyl-substituted with R33;
2-(H3CO)-phenyl-substituted with R33;
2-(fluoro)-phenyl-substituted with R33;
2-(chloro)-phenyl-substituted with R33;
3-(NC)-phenyl-substituted with R33;
3-(H3CO)-phenyl-substituted with R33;
3-(fluoro)-phenyl-substituted with R33;
3-(chloro)-phenyl-substituted with R33;
3-(H3C)-phenyl-substituted with R33;
3-(F3C)-phenyl-substituted with R33;
3-(H3CS)-phenyl-substituted with R33;
4-(NC)-phenyl-substituted with R33;
4-(fluoro)-phenyl-substituted with R33;
4-(chloro)-phenyl-substituted with R33;
4-(H3CS)-phenyl-substituted with R33;
4-(H3CO)-phenyl-substituted with R33;
4-(ethoxy)-phenyl-substituted with R33;
4-(i-propoxy)-phenyl-substituted with R33;
4-(i-butoxy)-phenyl-substituted with R33;
4-(H3CCH2CH2C(xe2x95x90O))-phenyl-substituted with R33;
4-((H3C)2CHC(xe2x95x90O))-phenyl-substituted with R33;
4-(H3CCH2C(xe2x95x90O))-phenyl-substituted with R33;
4-(H3CC(xe2x95x90O))-phenyl-substituted with R33;
4-(H3CCH2CH2CH(OH))-phenyl-substituted with R33;
4-((H3C)2CHCH(OH))-phenyl-substituted with R33;
4-(H3CCH2CH(OH))-phenyl-substituted with R33;
4-(H3CCH(OH))-phenyl-substituted with R33;
4-(cyclopropyloxy)-phenyl-substituted with R33;
4-(cyclobutyloxy)-phenyl-substituted with R33; and
4-(cyclopentyloxy)-phenyl-substituted with R33;
R12 is selected from
methyl substituted with R11;
phenyl substituted with 0-5 fluoro;
pyridyl substituted with 0-2 R33;
naphthyl substituted with 0-2 R33;
2-(H3CCH2C(xe2x95x90O))-phenyl-substituted with R33;
2-(H3CC(xe2x95x90O))-phenyl-substituted with R33;
2-(HC(xe2x95x90O))-phenyl-substituted with R33;
2-(H3CCH(OH))-phenyl-substituted with R33;
2-(H3CCH2CH(OH))-phenyl-substituted with R33;
2-(HOCH2)-phenyl-substituted with R33;
2-(HOCH2CH2)-phenyl-substituted with R33;
2-(H3OCCH2)-phenyl-substituted with R33;
2-(H3COCH2CH2)-phenyl-substituted with R33;
2-(H3CCH(OMe))-phenyl-substituted with R33;
2-(H3COC(xe2x95x90O))-phenyl-substituted with R33;
2-(HOCH2CHxe2x95x90CH)-phenyl-substituted with R33;
2-((MeOCxe2x95x90O)CHxe2x95x90CH)-phenyl-substituted with R33;
2-(methyl)-phenyl-substituted with R33;
2-(ethyl)-phenyl-substituted with R33;
2-(i-propyl)-phenyl-substituted with R33;
2-(F3C)-phenyl-substituted with R33;
2-(NC)-phenyl-substituted with R33;
2-(H3CO)-phenyl-substituted with R33;
2-(fluoro)-phenyl-substituted with R33;
2-(chloro)-phenyl-substituted with R33;
3-(NC)-phenyl-substituted with R33;
3-(H3CO)-phenyl-substituted with R33;
3-(fluoro)-phenyl-substituted with R33;
3-(chloro)-phenyl-substituted with R33;
3-(H3C)-phenyl-substituted with R33;
3-(F3C)-phenyl-substituted with R33;
3-(H3CS)-phenyl-substituted with R33;
4-(fluoro)-phenyl-substituted with R33;
4-(chloro)-phenyl-substituted with R33;
4-(H3CS)-phenyl-substituted with R33;
4-(H3CO)-phenyl-substituted with R33;
4-(ethoxy)-phenyl-substituted with R33;
4-(i-propoxy)-phenyl-substituted with R33;
4-(i-butoxy)-phenyl-substituted with R33;
4-(H3CCH2CH2C(xe2x95x90O))-phenyl-substituted with R33;
4-((H3C)2CHC(xe2x95x90O))-phenyl-substituted with R33;
4-((H3CCH2C(xe2x95x90O))-phenyl-substituted with R33;
4-(H3CC(xe2x95x90O))-phenyl-substituted with R33;
4-(H3CCH2CH2CH(OH))-phenyl-substituted with R33;
4-((H3C)2CHCH(OH))-phenyl-substituted with R33;
4-(H3CCH2CH(OH))-phenyl-substituted with R33;
4-(H3CCH(OH))-phenyl-substituted with R33;
4-(cyclopropyloxy)-phenyl-substituted with R33; 
4-(cyclobutyloxy)-phenyl-substituted with R33; and
4-(cyclopentyloxy)-phenyl-substituted with R33;
R13 is H, methyl, or ethyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring selected from pyrrolyl, pyrrolidinyl, imidazolyl, piperidinyl, piperizinyl, methylpiperizinyl,and morpholinyl;
alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S; wherein said bicyclic heterocyclic ring system is selected from indolyl, indolinyl, indazolyl, benzimidazolyl, benzimidazolinyl, benztriazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, and tetrahydroisoquinolinyl; wherein said bicyclic heterocyclic ring system is substituted with 0-1 R16;
R15 is H, methyl, ethyl, propyl, or butyl;
R16, at each occurrence, is independently selected from
H, OH, F, Cl, CN, NO2, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy;
R33, at each occurrence, is independently selected from
H, F, Cl, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94SCH3, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, and xe2x80x94NO2;
n is 1; and
m is 1.
[7] In an another embodiment, the present invention provides a novel compound of Formula (I-a): 
wherein:
b is a single bond wherein the bridging hydrogens are either cis or trans;
X is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94OCH2xe2x80x94, or xe2x80x94SCH2xe2x80x94;
R1 is selected from
hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl, 2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, 3-methylbutyl,
4-methylpentyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,
2-propenyl, 2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-2-butenyl, 3-butenyl, trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,
benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2,5-dimethylbenzyl, 2,4-dimethylbenzyl, 3,5-dimethylbenzyl, 2,4,6-trimethyl-benzyl, 3-methoxy-benzyl, 3,5-dimethoxy-benzyl, pentafluorobenzyl, 2-phenylethyl, 1-phenyl-2-propyl, 4-phenylbutyl, 4-phenylbenzyl, 2-phenylbenzyl,
(2,3-dimethoxy-phenyl)C(xe2x95x90O)xe2x80x94, (2,5-dimethoxy-phenyl)C(xe2x95x90O)xe2x80x94, (3,4-dimethoxy-phenyl)C(xe2x95x90O)xe2x80x94, (3,5-dimethoxy-phenyl)C(xe2x95x90O)xe2x80x94, cyclopropyl-C(xe2x95x90O)xe2x80x94, isopropyl-C(xe2x95x90O)xe2x80x94, ethyl-CO2xe2x80x94, propyl-CO2xe2x80x94, t-butyl-CO2xe2x80x94, 2,6-dimethoxy-benzyl, 2,4-dimethoxy-benzyl, 2,4,6-trimethoxy-benzyl, 2,3-dimethoxy-benzyl, 2,4,5-trimethoxy-benzyl, 2,3,4-trimethoxy-benzyl, 3,4-dimethoxy-benzyl, 3,4,5-trimethoxy-benzyl, (4-fluoro-phenyl)ethyl,
xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CHxe2x80x94CH3, xe2x80x94Cxe2x89xa1CH, xe2x80x94Cxe2x80x94Cxe2x89xa1CH3, and xe2x80x94CH2xe2x80x94Cxe2x89xa1CH; and
R6a is H;
R6b is H;
alternatively, R6a and R6b are taken together to form xe2x95x90O;
R7, R8, and R9, at each occurrence, are independently selected from
hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenyl;
2-Cl-phenyl; 2-F-phenyl; 2-Br-phenyl; 2-CN-phenyl; 2-Me-phenyl; 2-CF3-phenyl; 2-MeO-phenyl; 2-CF3O-phenyl; 2-NO2-phenyl; 2-MeS-phenyl; 2-CHO-phenyl; 2-HOCH2-phenyl;
3-Cl-phenyl; 3-F-phenyl; 3-Br-phenyl; 3-CN-phenyl; 3-Me-phenyl; 3-Et-phenyl; 3-n-Pr-phenyl; 3-isoPr-phenyl; 3-n-Bu-phenyl; 3-CF3-phenyl; 3-MeO-phenyl; 3-MeS-phenyl; 3-isopropoxyphenyl; 3-CF3O-phenyl; 3-NO2-phenyl; 3-CHO-phenyl; 3-HOCH2-phenyl; 3-MeOCH2-phenyl; 3-Me2NCH2-phenyl;
4-Cl-phenyl; 4-F-phenyl; 4-Br-phenyl; 4-CN-phenyl; 4-Me-phenyl; 4-Et-phenyl; 4-n-Pr-phenyl; 4-iso-Pr-phenyl; 4-n-Bu-phenyl; 4-CF3-phenyl; 4-MeO-phenyl; 4-isopropoxyphenyl; 4-CF3O-phenyl; 4-MeS-phenyl;
4-acetylphenyl; 3-acetamidophenyl; 4-pyridyl; 2-furanyl; 2-thiophenyl; 2-naphthyl; 1-pyrrolidinyl,
2,3-diCl-phenyl; 2,3-diF-phenyl; 2,3-diMe-phenyl; 2,3-diCF3-phenyl; 2,3-diMeo-phenyl; 2,3-diCF3O-phenyl;
2,4-diCl-phenyl; 2,4-diF-phenyl; 2,4-diMe-phenyl; 2,4-diCF3-phenyl; 2,4-diMeo-phenyl; 2,4-diCF3O-phenyl;
2,5-diCl-phenyl; 2,5-diF-phenyl; 2,5-diMe-phenyl; 2,5-diCF3-phenyl; 2,5-diMeO-phenyl; 2,5-diCF3O-phenyl;
2,6-diCl-phenyl; 2,6-diF-phenyl; 2,6-diMe-phenyl; 2,6-diCF3-phenyl; 2,6-diMeO-phenyl; 2,6-diCF3O-phenyl;
3,4-diCl-phenyl; 3,4-diF-phenyl; 3,4-diMe-phenyl; 3,4-diCF3-phenyl; 3,4-diMeO-phenyl; 3,4-diCF3O-phenyl;
2,4,6-triCl-phenyl; 2,4,6-triF-phenyl; 2,4,6-triMe-phenyl; 2,4,6-triCF3-phenyl; 2,4,6-triMeO-phenyl; 2,4,6-triCF3O-phenyl; 2,4,5-triMe-phenyl; 2,3,4-triF-phenyl; 2-Me-4-MeO-5-F-phenyl; 2,6-diCl-4-MeO-phenyl; 2,4-diMeO-6-F-phenyl; 2,6-diF-4-Cl-phenyl; 2,3,4,6-tetraF-phenyl; 2,3,4,5,6-pentaF-phenyl;
2-Cl-4-F-phenyl; 2-Cl-6-F-phenyl; 2-Cl-3-Me-phenyl; 2-Cl-4-MeO-phenyl; 2-Cl-4-EtO-phenyl; 2-Cl-4-iPrO-phenyl; 2-Cl-4-CF3-phenyl; 2-Cl-4-CF3O-phenyl; 2-Cl-4-(CHF2)O-phenyl; 2-F-3-Cl-phenyl; 2-F-4-MeO-phenyl; 2-F-5-Me-phenyl;
2-Me-3-Cl-phenyl; 2-Me-3-CN-phenyl; 2-Me-4-Cl-phenyl; 2-Me-4-F-phenyl; 2-Me-4-CN-phenyl; 2-Me-4-MeO-phenyl; 2-Me-4-EtO-phenyl; 2-Me-4-MeS-phenyl; 2-Me-4-H2NCO-phenyl; 2-Me-4-MeOC(xe2x95x90O)-phenyl; 2-Me-4-CH3C(xe2x95x90O)-phenyl; 2-Me-5-F-phenyl; 2-Et-4-MeO-phenyl; 2-MeO-S-F-phenyl; 2-Meo-4-isopropyl-phenyl; 2-CF3-4-Cl-phenyl; 2-CF3-4-F-phenyl; 2-CF3-4-MeO-phenyl; 2-CF3-4-EtO-phenyl; 2-CF3-4-iPrO-phenyl; 2-CF3-4-CN-phenyl; 2-CF3-6-F-phenyl; 2-CHO-4-MeO-phenyl; 2-MeOC(xe2x95x90O)-3-MeO-phenyl; 2-CH3CH(OH)-4-MeO-phenyl; 2-CH3CH(OH)-4-F-phenyl; 2-CH3CH(OH)-4-Cl-phenyl; 2-CH3CH(OH)-4-Me-phenyl; 2-CH3CH(OMe)-4-MeO-phenyl; 2-CH3C(xe2x95x90O)-4-MeO-phenyl; 2-CH3C(xe2x95x90O)-4-F-phenyl; 2-CH3C(xe2x95x90O)-4-Cl-phenyl; 2-CH3C(xe2x95x90O)-4-Me-phenyl; 2-H2C(OH)-4-MeO-phenyl;
2-H2C(OMe)-4-MeO-phenyl; 2-H3CCH2CH(OH)-4-MeO-phenyl; 2-H3CCH2C(xe2x95x90O)-4-MeO-phenyl; 2-CH3CO2CH2CH2-4-MeO-phenyl; (Z)-2-HOCH2CHxe2x95x90CH-4-MeO-phenyl; (E)-2-HOCH2CHxe2x95x90CH-4-MeO-phenyl; (Z)-2-CH3CO2CHxe2x95x90CH-4-MeO-phenyl; (E)-2-CH3CO2CHxe2x95x90CH-4-MeO-phenyl; 2-CH3OCH2CH2-4-MeO-phenyl;
3-CN-4-F-phenyl; 3-H2NCO-4-F-phenyl; (2-Cl-phenyl)-CHxe2x95x90CHxe2x80x94; (3-Cl-phenyl)-CHxe2x95x90CHxe2x80x94; (2,6-diF-phenyl)-CHxe2x95x90CHxe2x80x94; phenyl-CHxe2x95x90CHxe2x80x94; (2-Me-4-MeO-phenyl)-CHxe2x95x90CHxe2x80x94;
cyclohexyl; cyclopentyl; cyclohexylmethyl; benzyl; 2-F-benzyl; 3-F-benzyl; 4-F-benzyl; 3-MeO-benzyl; 3-OH-benzyl; 2-MeO-benzyl; 2-OH-benzyl; tetrahydroquinolin-1-yl; tetrahydroindolin-1-yl; tetrahydroisoindolin-1-yl;
phenyl-Sxe2x80x94; phenyl-NHxe2x80x94; pyrid-3-yl-NHxe2x80x94; (4-Me-pyrid-3-yl)-NHxe2x80x94; (4-Cl-pyrid-3-yl)-NHxe2x80x94; (1-naphthyl)-NHxe2x80x94; (2-naphthyl)-NHxe2x80x94; (2-Me-naphth-1-yl)-NHxe2x80x94; (4-Me-naphth-1-yl)-NHxe2x80x94; (3-quinolinyl)-NHxe2x80x94;
(2-[1,1xe2x80x2-biphenyl])-NHxe2x80x94; (3-[1,1xe2x80x2-biphenyl])-NHxe2x80x94; (4-[1,1xe2x80x2-biphenyl])-NHxe2x80x94; (2-F-phenyl)-NHxe2x80x94; (2-Cl-phenyl)-NHxe2x80x94; (2-CF3-phenyl)-NHxe2x80x94; (2-CH3-phenyl)-NHxe2x80x94; (2-OMe-phenyl)-NHxe2x80x94; (2-CN-phenyl)-NHxe2x80x94; (2-OCF3-phenyl)-NHxe2x80x94; (2-SMe-phenyl)-NHxe2x80x94; (3-F-phenyl)-NHxe2x80x94; (3-Cl-phenyl)-NHxe2x80x94; (3-CF3-phenyl)-NHxe2x80x94; (3-CH3-phenyl)-NHxe2x80x94; (3-OMe-phenyl)-NHxe2x80x94; (3-CN-phenyl)-NHxe2x80x94; (3-OCF3-phenyl)-NHxe2x80x94; (3-SMe-phenyl)-NHxe2x80x94; (4-F-phenyl)-NHxe2x80x94; (4-Cl-phenyl)-NHxe2x80x94; (4-CF3-phenyl)-NHxe2x80x94; (4-CH3-phenyl)-NHxe2x80x94; (4-OMe-phenyl)-NHxe2x80x94; (4-CN-phenyl)-NHxe2x80x94; (4-OCF3-phenyl)-NHxe2x80x94; (4-SMe-phenyl)-NHxe2x80x94; (2,3-diCl-phenyl)-NHxe2x80x94; (2,4-diCl-phenyl)-NHxe2x80x94; (2,5-diCl-phenyl)-NHxe2x80x94; (2,6-diCl-phenyl)-NHxe2x80x94; (3,4-diCl-phenyl)-NHxe2x80x94; (3,5-diCl-phenyl)-NHxe2x80x94; (2,3-diF-phenyl)-NHxe2x80x94; (2,4-diF-phenyl)-NHxe2x80x94; (2,5-diF-phenyl)-NHxe2x80x94; (2,6-diF-phenyl)-NHxe2x80x94; (3,4-diF-phenyl)-NHxe2x80x94; (3,5-diF-phenyl)-NHxe2x80x94; (2,3-diCH3-phenyl)-NHxe2x80x94; (2,4-diCH3-phenyl)-NHxe2x80x94; (2,5-diCH3-phenyl)-NHxe2x80x94; (2,6-diCH3-phenyl)-NHxe2x80x94; (3,4-diCH3-phenyl)-NHxe2x80x94; (3,5-diCH3-phenyl)-NHxe2x80x94; (2,3-diCF3-phenyl)-NHxe2x80x94; (2,4-diCF3-phenyl)-NHxe2x80x94; (2,5-diCF3-phenyl)-NHxe2x80x94; (2,6-diCF3-phenyl)-NHxe2x80x94; (3,4-diCF3-phenyl)-NHxe2x80x94; (3,5-diCF3-phenyl)-NHxe2x80x94; (2,3-diOMe-phenyl)-NHxe2x80x94; (2,4-diOMe-phenyl)-NHxe2x80x94; (2,5-diOMe-phenyl)-NHxe2x80x94; (2,6-diOMe-phenyl)-NHxe2x80x94; (3,4-diOMe-phenyl)-NHxe2x80x94; (3,5-diOMe-phenyl)-NHxe2x80x94; (2-F-3-Cl-phenyl)-NHxe2x80x94; (2-F-4-Cl-phenyl)-NHxe2x80x94; (2-F-5-Cl-phenyl)-NHxe2x80x94; (2-F-6-Cl-phenyl)-NHxe2x80x94; (2-F-3-CH3-phenyl)-NHxe2x80x94; (2-F-4-CH3-phenyl)-NHxe2x80x94; (2-F-5-CH3-phenyl)-NHxe2x80x94; (2-F-6-CH3-phenyl)-NHxe2x80x94; (2-F-3-CF3-phenyl)-NHxe2x80x94; (2-F-4-CF3-phenyl)-NHxe2x80x94; (2-F-5-CF3-phenyl)-NHxe2x80x94; (2-F-6-CF3-phenyl)-NHxe2x80x94; (2-F-3-OMe-phenyl)-NHxe2x80x94; (2-F-4-OMe-phenyl)-NHxe2x80x94; (2-F-5-OMe-phenyl)-NHxe2x80x94; (2-F-6-OMe-phenyl)-NHxe2x80x94; (2-CF-3-F-phenyl)-NHxe2x80x94; (2-Cl-4-F-phenyl)-NHxe2x80x94; (2-CF-5-F-phenyl)-NHxe2x80x94; (2-CF-6-F-phenyl)-NHxe2x80x94; (2-Cl-3-CH3-phenyl)-NHxe2x80x94; (2-Cl-4-CH3-phenyl)-NHxe2x80x94; (2-F-5-CH3-phenyl )-NHxe2x80x94; (2-Cl-6-CH3-phenyl)-NHxe2x80x94; (2-Cl-3-CF3-phenyl)-NHxe2x80x94; (2-Cl-4-CF3-phenyl)-NHxe2x80x94; (2-F-5-CF3-phenyl)-NHxe2x80x94; (2-Cl-6-CF3-phenyl)-NHxe2x80x94; (2-Cl-3-OMe-phenyl)-NHxe2x80x94; (2-Cl-4-OMe-phenyl)-NHxe2x80x94; (2-Cl-5-OMe-phenyl)-NHxe2x80x94; (2-Cl-6-OMe-phenyl)-NHxe2x80x94; (2-CH3-3-F-phenyl)-NHxe2x80x94; (2-CH3-4-F-phenyl)-NHxe2x80x94; (2-CH3-5-F-phenyl)-NHxe2x80x94; (2-CH3-6-F-phenyl)-NHxe2x80x94; (2-CH3-3-Cl-phenyl)-NHxe2x80x94; (2-CH3-4-Cl-phenyl)-NHxe2x80x94; (2-CH3-5-Cl-phenyl)-NHxe2x80x94; (2-CH3-6-Cl-phenyl)-NHxe2x80x94; (2-CH3-3-CF3-phenyl)-NHxe2x80x94; (2-CH3-4-CF3-phenyl)-NHxe2x80x94; (2-CH3-5-CF3-phenyl)-NHxe2x80x94; (2-CH3-6-CF3-phenyl)-NHxe2x80x94; (2-CH3-3-OMe-phenyl)-NHxe2x80x94; (2-CH3-4-OMe-phenyl)-NHxe2x80x94; (2-CH3-5-OMe-phenyl)-NHxe2x80x94; (2-CH3-6-OMe-phenyl)-NHxe2x80x94; (2-CF3-3-F-phenyl)-NHxe2x80x94; (2-CF3-4-F-phenyl)-NHxe2x80x94; (2-CF3-5-F-phenyl)-NHxe2x80x94; (2-CF3-6-F-phenyl)-NHxe2x80x94; (2-CF3-3-Cl-phenyl)-NHxe2x80x94; (2-CF3-4-Cl-phenyl)-NHxe2x80x94; (2-CF3-5-Cl-phenyl)-NHxe2x80x94; (2-CF3-6-Cl-phenyl)-NHxe2x80x94; (2-CF3-3-CH3-phenyl)-NHxe2x80x94; (2-CF3-4-CH3-phenyl)-NHxe2x80x94; (2-CH3-5-C,F3-phenyl)-NHxe2x80x94; (2-CF3-6-CH3-phenyl)-NHxe2x80x94; (2-CF3-3-OMe-phenyl)-NHxe2x80x94; (2-CF3-4-OMe-phenyl)-NHxe2x80x94; (2-CF3-5-OMe-phenyl)-NHxe2x80x94; (2-CF3-6-OMe-phenyl)-NHxe2x80x94; (2-OMe-3-F-phenyl)-NHxe2x80x94; (2-OMe-4-F-phenyl)-NHxe2x80x94; (2-OMe-5-F-phenyl)-NHxe2x80x94; (2-OMe-6-F-phenyl)-NHxe2x80x94; (2-OMe-3-Cl-phenyl)-NHxe2x80x94; (2-OMe-4-Cl-phenyl)-NHxe2x80x94; (2-OMe-5-Cl-phenyl)-NHxe2x80x94; (2-OMe-6-Cl-phenyl)-NHxe2x80x94; (2-OMe-4-CN-phenyl)-NHxe2x80x94; (2-OMe-4-CHO-phenyl)-NHxe2x80x94; (2-OMe-3-CH3-phenyl)-NHxe2x80x94; (2-OMe-4-CH3-phenyl)-NHxe2x80x94; (2-OMe-5-CH3-phenyl)-NHxe2x80x94; (2-OMe-6-CH3-phenyl)-NHxe2x80x94; (2-OMe-3-CF3-phenyl)-NHxe2x80x94; (2-OMe-4-CF3-phenyl)-NHxe2x80x94; (2-OMe-5-CF3-phenyl)-NHxe2x80x94; (2-OMe-6-CF3-phenyl)-NHxe2x80x94; (2-acetyl-4-Cl-phenyl)-NHxe2x80x94; (2-acetyl-4-Me-phenyl)-NHxe2x80x94; (2-acetyl-4-MeO-phenyl)-NHxe2x80x94; (2-CH3CH(OH)-4-Cl-phenyl)-NHxe2x80x94; (2-CH3CH(OH)-4-Me-phenyl)-NHxe2x80x94; (2-CH3CH(OH)-4-MeO-phenyl)-NHxe2x80x94;
(3-CF3-4-Cl-phenyl)-NHxe2x80x94; (3-F-4-CHO-phenyl)-NHxe2x80x94; (3-CH3-4-CN-phenyl)-NHxe2x80x94; (3-CH3-4-MeO-phenyl)-NHxe2x80x94; (3-CH3-4-Cl-phenyl)-NHxe2x80x94; (3-CH3-4-F-phenyl)-NHxe2x80x94; (3-F-5-CF3-phenyl)-NHxe2x80x94;
(3-CH3-4-CO2Me-phenyl)NHxe2x80x94; (3-CF3-4-C(O)CH3-phenyl)NHxe2x80x94; (3-CHO-4-OMe-phenyl)-NHxe2x80x94; (4-F-3-CF3-phenyl)-NHxe2x80x94;
(2,3,5-triCl-phenyl)-NHxe2x80x94; (2,4,5-triF-phenyl)-NHxe2x80x94; (2,6-diCl-3-Me-phenyl)-NHxe2x80x94; (3,5-diMe-4-MeO-phenyl)-NHxe2x80x94; (2-F-3-Cl-6-CF3-phenyl)-NHxe2x80x94;
bynzyl-NHxe2x80x94; (3-quinolinyl)CH2NHxe2x80x94; (2-F-phenyl)CH2NHxe2x80x94; (2-Cl-phenyl)CH2NHxe2x80x94; (2-CF3-phenyl)CH2NHxe2x80x94; (2-CH3-phenyl)CH2NHxe2x80x94; (2-OMe-phenyl)CH2NHxe2x80x94; (2-CN-phenyl)CH2NHxe2x80x94; (2-OCF3-phenyl)CH2NHxe2x80x94; (2-SMe-phenyl)CH2NHxe2x80x94; (3-F-phenyl)CH2NHxe2x80x94; (3-Cl-phenyl)CH2NHxe2x80x94; (3-CF3-phenyl)CH2NHxe2x80x94; (3-CH3-phenyl)CH2NHxe2x80x94; (3-OMe-phenyl)CH2NHxe2x80x94; (3-CN-phenyl)CH2NHxe2x80x94; (3-OCF3-phenyl)CH2NHxe2x80x94; (3-SMe-phenyl)CH2NHxe2x80x94; (4-F-phenyl)CH2NHxe2x80x94; (4-Cl-phenyl)CH2NHxe2x80x94; (4-CF3-phenyl)CH2NHxe2x80x94; (4-CH3-phenyl)CH2NHxe2x80x94; (4OMe-phenyl)CH2NHxe2x80x94; (4-CN-phenyl)CH2NHxe2x80x94; (4-OCF3-phenyl)CH2NHxe2x80x94; (4-SMe-phenyl)CH2NHxe2x80x94; (2,3-diClphenyl)CH2NHxe2x80x94; (2,4-diCl-phenyl)CH2NHxe2x80x94; (2,5-diCl-phenyl)CH2NHxe2x80x94; (2,6-diCl-phenyl)CH2NHxe2x80x94; (3,4-diCl-phenyl)CH2NHxe2x80x94; (3,5-diCl-phenyl)CH2NHxe2x80x94; (2,3-diF-phenyl)CH2NHxe2x80x94; (2,4-diF-phenyl)CH2NHxe2x80x94; (2,5-diF-phenyl)CH2NHxe2x80x94; (2,6-diF-phenyl)CH2NHxe2x80x94; (3,4-diF-phenyl)CH2NHxe2x80x94; (3,5-diF-phenyl)CH2NHxe2x80x94; (2,3-diCH3-phenyl)CH2NHxe2x80x94; (2,4-diCH3-phenyl)CH2NHxe2x80x94; (2,5-diCH3-phenyl)CH2NHxe2x80x94; (2,6-diCH3-phenyl)CH2NHxe2x80x94; (3,4-diCH3-phenyl)CH2NHxe2x80x94; (3,5-diCH3-phenyl)CH2NHxe2x80x94; (2,3-diCF3-phenyl)CH2NHxe2x80x94; (2,4-diCF3-phenyl)CH2NHxe2x80x94; (2,5-diCF3-phenyl)CH2NHxe2x80x94; (2,6-diCF3-phenyl)CH2NHxe2x80x94; (3,4-diCF3-phenyl)CH2NHxe2x80x94; (3,5-diCF3-phenyl)CH2NHxe2x80x94; (2,3-diOMe-phenyl)CH2NHxe2x80x94; (2,4-diOMe-phenyl)CH2NHxe2x80x94; (2,5-diOMe-phenyl)CH2NHxe2x80x94; (2,6-diOMe-phenyl)CH2NHxe2x80x94; (3,4-diOMe-phenyl)CH2NHxe2x80x94; (3,5-diOMe-phenyl)CH2NHxe2x80x94; (2-F-3-Cl-phenyl)CH2NHxe2x80x94; (2-F-4-Cl-phenyl)CH2NHxe2x80x94; (2-F-5-Cl-phenyl)CH2NHxe2x80x94; (2-F-6-Cl-phenyl)CH2NHxe2x80x94; (2-F-3-CH3-phenyl)CH2NHxe2x80x94; (2-F-4-CH3-phenyl)CH2NHxe2x80x94; (2-F-5-CH3-phenyl)CH2NHxe2x80x94; (2-F-6-CH3-phenyl)CH2NHxe2x80x94; (2-F-3-CF3-phenyl)CH2NHxe2x80x94; (2-F-4-CF3-phenyl)CH2NHxe2x80x94; (2-F-5-CF3-phenyl)CH2NHxe2x80x94; (2-F-6-CF3-phenyl)CH2NHxe2x80x94; (2-F-3-OMe-phenyl)CH2NHxe2x80x94; (2-F-4-OMe-phenyl)CH2NHxe2x80x94; (2-F-5-OMe-phenyl)CH2NHxe2x80x94; (2-F-6-OMe-phenyl)CH2NHxe2x80x94; (2-Cl-3-F-phenyl)CH2NHxe2x80x94; (2-Cl-4-F-phenyl)CH2NHxe2x80x94; (2-Cl-5-F-phenyl)CH2NHxe2x80x94; (2-Cl-6-F-phenyl)CH2NHxe2x80x94; (2-Cl-3-CH3-phenyl)CH2NHxe2x80x94; (2-Cl-4-CH3-phenyl)CH2NHxe2x80x94; (2-Cl-5-CH3-phenyl)CH2NHxe2x80x94; (2-Cl-6-CH3-phenyl)CH2NHxe2x80x94; (2-Cl-3-CF3-phenyl)CH2NHxe2x80x94; (2-Cl-4-CF3-phenyl)CH2NHxe2x80x94; (2-F-5-CF3-phenyl)CH2NHxe2x80x94; (2-Cl-6-CF3-phenyl)CH2NHxe2x80x94; (2-Cl-3-OMe-phenyl)CH2NHxe2x80x94; (2-Cl-4-OMe-phenyl)CH2NHxe2x80x94; (2-Cl-5-OMe-phenyl)CH2NHxe2x80x94; (2-Cl-6-OMe-phenyl)CH2NHxe2x80x94; (2-CH3-3-F-phenyl)CH2NHxe2x80x94; (2-CH3-4-F-phenyl)CH2NHxe2x80x94; (2-CH3-5-F-phenyl)CH2NHxe2x80x94; (2-CH3-6-F-phenyl)CH2NHxe2x80x94; (2-CH3-3-Cl-phenyl)CH2NHxe2x80x94; (2-CH3-4-Cl-phenyl)CH2NHxe2x80x94; (2-CH3-5-Cl-phenyl)CH2NHxe2x80x94; (2-CH3-6-Cl-phenyl)CH2NHxe2x80x94; (2-CH3-3-CF3-phenyl)CH2NHxe2x80x94; (2-CH3-4-CF3-phenyl)CH2NHxe2x80x94; (2-CH3-5-CF3-phenyl)CH2NHxe2x80x94; (2-CH3-6-CF3-phenyl)CH2NHxe2x80x94; (2-CH3-3-OMe-phenyl)CH2NHxe2x80x94; (2-CH3-4-OMe-phenyl)CH2NHxe2x80x94; (2-CH3-5-OMe-phenyl)CH2NHxe2x80x94; (2-CH3-6-OMe-phenyl)CH2NHxe2x80x94; (2-CF3-3-F-phenyl)CH2NHxe2x80x94; (2-CF3-4-F-phenyl)CH2NHxe2x80x94; (2-CF3-5-F-phenyl)CH2NHxe2x80x94; (2-CF3-6-F-phenyl)CH2NHxe2x80x94; (2-CF3-3-Cl-phenyl)CH2NHxe2x80x94; (2-CF3-4-Cl-phenyl)CH2NHxe2x80x94; (2-CF3-5-Cl-phenyl)CH2NHxe2x80x94; (2-CF3-6-Cl-phenyl)CH2NHxe2x80x94; (2-CF3-3-CH3-phenyl)CH2NHxe2x80x94; (2-CF3-4-CH3-phenyl)CH2NHxe2x80x94; (2-CH3-5-CF3-phenyl)CH2NHxe2x80x94; (2-CF3-6-CH3-phenyl)CH2NHxe2x80x94; (2-CF3-3-OMe-phenyl)CH2NHxe2x80x94; (2-CF3-4-OMe-phenyl)CH2NHxe2x80x94; (2-CF3-5-OMe-phenyl)CH2NHxe2x80x94; (2.-CF3-6-OMe-phenyl)CH2NHxe2x80x94; (2-OMe-3-F-phenyl)CH2NHxe2x80x94; (2-OMe-4-F-phenyl)CH2NHxe2x80x94; (2-OMe- 5-F-phenyl)CH2NHxe2x80x94; (2-OMe-6-F-phenyl)CH2NHxe2x80x94; (2-OMe-3-Cl-phenyl)CH2NHxe2x80x94; (2-OMe-4-Cl-phenyl)CH2NHxe2x80x94; (2-OMe-5-Cl-phenyl)CH2NHxe2x80x94; (2-OMe-6-Cl-phenyl)CH2NHxe2x80x94; (2-OMe-4-CN-phenyl)CH2NHxe2x80x94; (2-OMe-4-CHO-phenyl)CH2NHxe2x80x94; (2-OMe-3-CH3-phenyl)CH2NHxe2x80x94; (2-OMe-4-CH3-phenyl)CH2NHxe2x80x94; (2-OMe-5-CH3-phenyl)CH2NHxe2x80x94; (2-OMe-6-CH3-phenyl)CH2NHxe2x80x94; (2-OMe-3-CF3-phenyl)CH2NHxe2x80x94; (2-OMe-4-CF3-phenyl)CH2NHxe2x80x94; (2-OMe-5-CF3-phenyl)CH2NHxe2x80x94; (2-OMe-6-CF3-phenyl)CH2NHxe2x80x94; (2-acetyl-4-Cl-phenyl)CH2NHxe2x80x94; (2-acetyl-4-Me-phenyl)CH2NHxe2x80x94; (2-acetyl-4-MeO-phenyl)CH2NHxe2x80x94; (2-CH3CH(OH)-4-Cl-phenyl)CH2NHxe2x80x94; (2-CH3CH(OH)-4-Me-phenyl)CH2NHxe2x80x94; (2-CH3CH(OH)-4-MeO-phenyl)CH2NHxe2x80x94;
(3-CF3-4-Cl-phenyl)CH2NHxe2x80x94; (3-F-4-CHO-phenyl)CH2NHxe2x80x94; (3-CH3-4-CN-phenyl)CH2NHxe2x80x94; (3-CH3-4-MeO-phenyl)CH2NHxe2x80x94; (3-CH3-4-Cl-phenyl)CH2NHxe2x80x94; (3-CH3-4-F-phenyl)CH2NHxe2x80x94; (4-F-3-CF3-phenyl)CH2NHxe2x80x94; (3-CH3-4-CO2Me-phenyl)CH2NHxe2x80x94; (3-CF3-4-C(O)CH3-phenyl)CH2NHxe2x80x94; (3-CHO-4-OMe-phenyl)CH2NHxe2x80x94;
(2,3,5-triCl-phenyl)CH2NHxe2x80x94; (2,4,5-triF-phenyl)CH2NHxe2x80x94; (2,6-diCl-3-Me-phenyl)CH2NHxe2x80x94; (3,5-diMe-4-MeO-phenyl)CH2NHxe2x80x94; and (2-F-3-Cl-6-CF3-phenyl)CH2NHxe2x80x94;
provided that two of R7, R8, and R9, are independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
[8] In an another embodiment, the present invention provides a novel compound of Formula (II): 
wherein:
b is a single bond, wherein the bridge hydrogens are in a cis or trans position;
R1 is selected from
hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl, 2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, 3-methylbutyl, 4-methylpentyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl, 2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-2-butenyl, 3-butenyl, trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CHxe2x80x94CH3, xe2x80x94Cxe2x89xa1CH, xe2x80x94Cxe2x89xa1xe2x80x94Cxe2x80x94CH3, and xe2x80x94CH2xe2x80x94Cxe2x89xa1CH;
R6a is H;
R6b is H;
alternatively, R6a and R6b are taken together to form xe2x95x90O;
R7 and R9, at each occurrence, are independently selected from hydrogen, fluoro, methyl, trifluoromethyl, and methoxy;
R8 is selected from
hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenyl;
2-Cl-phenyl; 2-F-phenyl; 2-Br-phenyl; 2-CN-phenyl; 2-Me-phenyl; 2-CF3-phenyl; 2-MeO-phenyl; 2-CF3O-phenyl; 2-NO2-phenyl; 2-MeS-phenyl; 2-CHO-phenyl; 2-HOCH2-phenyl;
3-Cl-phenyl; 3-F-phenyl; 3-Br-phenyl; 3-CN-phenyl;
3-Me-phenyl; 3-Et-phenyl; 3-n-Pr-phenyl; 3-isoPr-phenyl; 3-n-Bu-phenyl; 3-CF3-phenyl; 3-MeO-phenyl; 3-MeS-phenyl; 3-isopropoxyphenyl; 3-CF3O-phenyl; 3-NO2-phenyl; 3-CHO-phenyl; 3-HOCH2-phenyl; 3-MeOCH2-phenyl; 3-Me2NCH2-phenyl;
4-Cl-phenyl; 4-F-phenyl; 4-Br-phenyl; 4-CN-phenyl; 4-Me-phenyl; 4-Et-phenyl; 4-n-Pr-phenyl; 4-iso-Pr-phenyl; 4-n-Bu-phenyl; 4-CF3-phenyl; 4-MeO-phenyl; 4-isopropoxyphenyl; 4-CF3O-phenyl; 4-MeS-phenyl;
4-acetylphenyl; 3-acetamidophenyl; 4-pyridyl; 2-furanyl; 2-thiophenyl; 2-naphthyl; 1-pyrrolidinyl,
2,3-diCl-phenyl; 2,3-diF-phenyl; 2,3-diMe-phenyl; 2,3-diCF3-phenyl; 2,3-diMeo-phenyl; 2,3-diCF3O-phenyl;
2,4-diCl-phenyl; 2,4-diF-phenyl; 2,4-diMe-phenyl; 2,4-diCF3-phenyl; 2,4-diMeo-phenyl; 2,4-diCF3O-phenyl;
2,5-diCl-phenyl; 2,5-dir-phenyl; 2,5-diMe-phenyl; 2, 5-diCF3-phenyl; 2, 5-diMeo-phenyl; 2, 5-diCF3O-phenyl;
2,6-diCl-phenyl; 2,6-diF-phenyl; 2,6-diMe-phenyl; 2,6-diCF3-phenyl; 2,6-diMeo-phenyl; 2,6-diCF3O-phenyl;
3,4-diCl-phenyl; 3,4-diF-phenyl; 3,4-diMe-phenyl; 3,4-diCF3-phenyl; 3,4-diMeO-phenyl; 3,4-diCF3O-phenyl;
2,4,6-triCl-phenyl; 2,4,6-triF -phenyl; 2,4,6-triMe-phenyl; 2,4,6-triCF3-phenyl; 2,4,6-triMeo-phenyl; 2,4,6-triCF3O-phenyl; 2,4,5-triMe-phenyl; 2,3,4-triF-phenyl; 2-Me-4-Meo-F-phenyl; 2,6-diCl-4-Meo- phenyl; 2,4-diMeo-6-F-phenyl; 2,6-diF-4-Cl- phenyl; 2,3,4,6-tetraF-phenyl; 2,3,4,5,6-pentaF-phenyl; 2-Cl-4-F-phenyl; 2-Cl-6-F-phenyl; 2-Cl-3-Me-phenyl; 2-Cl-4-MeO-phenyl; 2-Cl-4-EtO-phenyl; 2-Cl-4-iPrO-phenyl; 2-Cl-4-CF3-phenyl; 2-Cl-4-CF3O-phenyl; 2-Cl-4-(CHF2)O-phenyl; 2-F-3-Cl-phenyl; 2-F-4-MeO-phenyl; 2-F-5-Me-phenyl;
2-Me-3-Cl-phenyl; 2-Me-3-CN-phenyl; 2-Me-4-Cl-phenyl; 2-Me-4-F-phenyl; 2-Me-4-CN-phenyl; 2-Me-4-MeO-phenyl; 2-Me-4-EtO-phenyl; 2-Me-4-MeS-phenyl; 2-Me-4-H2NCO-phenyl; 2-Me-4-MeOC(xe2x95x90O)-phenyl; 2-Me-4-CH3C(xe2x95x90O)-phenyl; 2-Me-5-F-phenyl; 2-Et-4-MeO-phenyl; 2-MeO-5-F-phenyl; 2-MeO-4-isopropyl-phenyl; 2-CF3-4-Cl-phenyl; 2-CF3-4-F-phenyl; 2-CF3-4-MeO-phenyl; 2-CF3-4-EtO-phenyl; 2-CF3-4-iPrO-phenyl; 2-CF3-4-CN-phenyl; 2-CF3-6-F-phenyl; 2-CHO-4-MeO-phenyl; 2-MeOC(xe2x95x90O)-3-MeO-phenyl; 2-CH3CH(OH)-4-MeO-phenyl; 2-CH3CH(OH)-4-F-phenyl; 2-CH3CH(OH)-4-Cl-phenyl; 2-CH3CH(OH)-4-Me-phenyl; 2-CH3CH(OMe)-4-MeO-phenyl; 2-CH3C(xe2x95x90O)-4-MeO-phenyl; 2-CH3C(xe2x95x90O)-4-F-phenyl; 2-CH3C(xe2x95x90O)-4-Cl-phenyl; 2-CH3C(xe2x95x90O)-4-Me-phenyl; 2-H2C(OH)-4-MeO-phenyl; 2-H2C(OMe)-4-MeO-phenyl; 2-H3CCH2CH(OH)-4-MeO-phenyl; 2-H3CCH2C(xe2x95x90O)-4-MeO-phenyl; 2-CH3CO2CH2CH2-4-MeO-phenyl; (Z)-2-HOCH2CHxe2x95x90CH-4-MeO-phenyl; (E)-2-HOCH2CHxe2x95x90CH-4-MeO-phenyl; (Z)-2-CH3CO2CHxe2x95x90CH-4-MeO-phenyl; (E)-2-CH3CO2CHxe2x95x90CH-4-MeO-phenyl; 2-CH3OCH2CH2-4-MeO-phenyl;
3-CN-4-F-phenyl; 3-H2NCO-4-F-phenyl; (2-Cl-phenyl)-CHxe2x95x90CHxe2x80x94; (3-Cl-phenyl)-CHxe2x95x90CHxe2x80x94; (2,6-diF-phenyl)-CHxe2x95x90CHxe2x80x94; phenyl-CHxe2x95x90CHxe2x80x94; (2-Me-4-MeO-phenyl)-CHxe2x95x90CHxe2x80x94;
cyclohexyl; cyclopentyl; cyclohexylmethyl; benzyl; 2-F-benzyl; 3-F-benzyl; 4-F-benzyl; 3-MeO-benzyl; 3-OH-benzyl; 2-MeO-benzyl; 2-OH-benzyl; tetrahydroquinolin-1-yl; tetrahydroindolin-1-yl; tetrahydroisoindolin-1-yl;
phenyl-Sxe2x80x94; phenyl-NHxe2x80x94; pyrid-3-yl-NHxe2x80x94; (4-Me-pyrid-3-yl)-NHxe2x80x94; (4-Cl-pyrid-3-yl)-NHxe2x80x94; (1-naphthyl)-NHxe2x80x94; (2-naphthyl)-NHxe2x80x94; (2-Me-naphth-1-yl)-NHxe2x80x94; (4-Me-naphth-1-yl)-NHxe2x80x94; (3-quinolinyl)-NHxe2x80x94;
(2-[1,1xe2x80x2-biphenyl])-NHxe2x80x94; (3-[1,1xe2x80x2-biphenyl])-NHxe2x80x94; (4-[1,1xe2x80x2-biphenyl])-NHxe2x80x94; (2-F-phenyl)-NHxe2x80x94; (2-Cl-phenyl)-NHxe2x80x94; (2-CF3-phenyl)-NHxe2x80x94; (2-CH3-phenyl)-NHxe2x80x94; (2-OMe-phenyl)-NHxe2x80x94; (2-CN-phenyl)-NHxe2x80x94; (2-OCF3-phenyl)-NHxe2x80x94; (2-SMe-phenyl)-NHxe2x80x94; (3-F-phenyl)-NHxe2x80x94; (3-Cl-phenyl)-NHxe2x80x94; (3-CF3-phenyl)-NHxe2x80x94; (3-CH3-phenyl)-NHxe2x80x94; (3-OMe-phenyl)-NHxe2x80x94; (3-CN-phenyl)-NHxe2x80x94; (3-OCF3-phenyl)-NHxe2x80x94; (3-SMe-phenyl)-NHxe2x80x94; (4-F-phenyl)-NHxe2x80x94; (4-Cl-phenyl)-NHxe2x80x94; (4-CF3-phenyl)-NHxe2x80x94; (4-CH3-phenyl)-NHxe2x80x94; (4-OMe-phenyl)-NHxe2x80x94; (4-CN-phenyl)-NHxe2x80x94; (4-OCF3-phenyl)-NHxe2x80x94; (4-SMe-phenyl)-NHxe2x80x94; (2,3-diCl-phenyl)-NHxe2x80x94; (2,4-diCl-phenyl)-NHxe2x80x94; (2,5-diCl-phenyl)-NHxe2x80x94; (2,6-diCl-phenyl)-NHxe2x80x94; (3,4-diCl-phenyl)-NHxe2x80x94; (3,5-diCl-phenyl)-NHxe2x80x94; (2,3-diF-phenyl)-NHxe2x80x94; (2,4-diF-phenyl)-NHxe2x80x94; (2,5-diF-phenyl)-NHxe2x80x94; (2,6-diF-phenyl)-NHxe2x80x94; (3,4-diF-phenyl)-NHxe2x80x94; (3,5-diF-phenyl)-NHxe2x80x94; (2,3-diCH3-phenyl)-NHxe2x80x94; (2,4-diCH3-phenyl)-NHxe2x80x94; (2,5-diCH3-phenyl)-NHxe2x80x94; (2,6-diCH3-phenyl)-NHxe2x80x94; (3,4-diCH3-phenyl)-NHxe2x80x94; (3,5-diCH3-phenyl)-NHxe2x80x94; (2,3-diCF3-phenyl)-NHxe2x80x94; (2,4-diCF3-phenyl)-NHxe2x80x94; (2,5-diCF3-phenyl)-NHxe2x80x94; (2,6-diCF3-phenyl)-NHxe2x80x94; (3,4-diCF3-phenyl)-NHxe2x80x94; (3,5-diCF3-phenyl)-NHxe2x80x94; (2,3-diOMe-phenyl)-NHxe2x80x94; (2,4-diOMe-phenyl)-NHxe2x80x94; (2,5-diOMe-phenyl)-NHxe2x80x94; (2,6-diOMe-phenyl)-NHxe2x80x94; (3,4-diOMe-phenyl)-NHxe2x80x94; (3,5-diOMe-phenyl)-NHxe2x80x94; (2-F-3-Cl-phenyl)-NHxe2x80x94; (2-F-4-Cl-phenyl)-NHxe2x80x94; (2-F-5-Cl-phenyl)-NHxe2x80x94; (2-F-6-Cl-phenyl)-NHxe2x80x94; (2-F-3-CH3-phenyl)-NHxe2x80x94; (2-F-4-CH3-phenyl)-NHxe2x80x94; (2-F-5-CH3-phenyl)-NHxe2x80x94; (2-F-6-CH3-phenyl)-NHxe2x80x94; (2-F-3-CF3-phenyl)-NHxe2x80x94; (2-F-4-CF3-phenyl)-NHxe2x80x94; (2-F-5-CF3-phenyl)-NHxe2x80x94; (2-F-6-CF3-phenyl)-NHxe2x80x94; (2-F-3-OMe-phenyl)-NHxe2x80x94; (2-F-4-OMe-phenyl)-NHxe2x80x94; (2-F-5-OMe-phenyl)-NHxe2x80x94; (2-F-6-OMe-phenyl)-NHxe2x80x94; (2-Cl-3-F-phenyl)-NHxe2x80x94; (2-Cl-4-F-phenyl)-NHxe2x80x94; (2-Cl-5-F-phenyl)-NHxe2x80x94; (2-Cl-6-F-phenyl)-NHxe2x80x94; (2-Cl-3-CH3-phenyl)-NHxe2x80x94; (2-Cl-4-CH3-phenyl)-NHxe2x80x94; (2-Cl-Sxe2x80x94CH3-phenyl)-NHxe2x80x94; (2-Cl-6-CH3-phenyl)-NHxe2x80x94; (2-Cl-3-CF3-phenyl)-NHxe2x80x94; (2-Cl-4-CF3-phenyl)-NHxe2x80x94; (2-F-5-CF3-phenyl)-NHxe2x80x94; (2-Cl-6-CF3-phenyl)-NHxe2x80x94; (2-Cl-3-OMe-phenyl)-NHxe2x80x94; (2-Cl-4-OMe-phenyl)-NHxe2x80x94; (2-Cl-5-OMe-phenyl)-NHxe2x80x94; (2-Cl-6-OMe-phenyl)-NHxe2x80x94; (2-CH3-3-F-phenyl)-NHxe2x80x94; (2-CH3-4-F-phenyl)-NHxe2x80x94; (2-CH3-5-F-phenyl)-NHxe2x80x94; (2-CH3-6-F-phenyl)-NHxe2x80x94; (2-CH3-3-Cl-phenyl)-NHxe2x80x94; (2-CH3-4-Cl-phenyl)-NHxe2x80x94; (2-CH3-5-Cl-phenyl)-NHxe2x80x94; (2-CH3-6-Cl-phenyl)-NHxe2x80x94; (2-CH3-3-CF3-phenyl)-NHxe2x80x94; (2-CH3-4-CF3-phenyl)-NHxe2x80x94; (2-CH3-5-CF3-phenyl)-NHxe2x80x94; (2-CH3-6-CF3-phenyl)-NHxe2x80x94; (2-CH3-3-OMe-phenyl)-NHxe2x80x94; (2-CH3-4-OMe-phenyl)-NHxe2x80x94; (2-CH3-5-OMe-phenyl)-NHxe2x80x94; (2-CH3-6-OMe-phenyl)-NHxe2x80x94; (2-CF3-3-F-phenyl)-NHxe2x80x94; (2-CF3-4-F-phenyl)-NHxe2x80x94; (2-CF3-5-F-phenyl)-NHxe2x80x94; (2-CF3-6-F-phenyl)-NHxe2x80x94; (2-CF3-3-Cl-phenyl)-NHxe2x80x94; (2-CF3-4-Cl-phenyl)-NHxe2x80x94; (2-CF3-5-Cl-phenyl)-NHxe2x80x94; (2-CF3-6-Cl-phenyl)-NHxe2x80x94; (2-CF3-3-CH3-phenyl)-NHxe2x80x94; (2-CF3-4-CH3-phenyl)-NHxe2x80x94; (2-CH3-5-CF3-phenyl)-NHxe2x80x94; (2-CF3-6-CH3-phenyl)-NHxe2x80x94; (2-CF3-3-OMe-phenyl)-NHxe2x80x94; (2-CF3-4-OMe-phenyl)-NHxe2x80x94; (2-CF3-5-OMe-phenyl)-NHxe2x80x94; (2-CF3-6-OMe-phenyl)-NHxe2x80x94; (2-OMe-3-F-phenyl)-NHxe2x80x94; (2-OMe-4-F-phenyl)-NHxe2x80x94; (2-OMe-5-F-phenyl)-NHxe2x80x94; (2-OMe-6-F-phenyl)-NHxe2x80x94; (2-OMe-3-Cl-phenyl)-NHxe2x80x94; (2-OMe-4-Cl-phenyl)-NHxe2x80x94; (2-OMe-5-Cl-phenyl)-NHxe2x80x94; (2-OMe-6-Cl-phenyl)-NHxe2x80x94; (2-OMe-4-CN-phenyl)-NHxe2x80x94; (2-OMe-4-CHO-phenyl)-NHxe2x80x94; (2-OMe-3-CH3-phenyl)-NHxe2x80x94; (2-OMe-4-CH3-phenyl)-NHxe2x80x94; (2-OMe-5-CH3-phenyl)-NHxe2x80x94; (2-OMe-6-CH3-phenyl)-NHxe2x80x94; (2-OMe-3-CF3-phenyl)-NHxe2x80x94; (2-OMe-4-CF3-phenyl)-NHxe2x80x94; (2-OMe-5-CF3-phenyl)-NHxe2x80x94; (2-OMe-6-CF3-phenyl)-NHxe2x80x94; (2-acetyl-4-C1-phenyl)-NHxe2x80x94; (2-acetyl-4-Me-phenyl)-NHxe2x80x94; (2-acetyl-4-MeO-phenyl)-NHxe2x80x94; (2-CCH3CH(OH)-4-Cl-phenyl)-NHxe2x80x94; (2-CH3CH(OH)-4-Me-phenyl)-NHxe2x80x94; (2-CH3CH(OH)-4-MeO-phenyl)-NHxe2x80x94;
(3-CF3-4-Cl-phenyl)-NHxe2x80x94; (3-F-4-CHO-phenyl)-NHxe2x80x94; (3-CH3-4-CN-phenyl)-NHxe2x80x94; (3-CH3-4-MeO-phenyl)-NHxe2x80x94; (3-CH3-4-Cl-phenyl)-NHxe2x80x94; (3-CH3-4-F-phenyl)-NHxe2x80x94; (3-F-5-CF3-phenyl)-NHxe2x80x94;
(3-CH3-4-CO2Me-phenyl)NHxe2x80x94; (3-CF3-4-C(O)CH3-phenyl)NHxe2x80x94; (3-CHO-4-OMe-phenyl)-NHxe2x80x94; (4-F-3-CF3-phenyl)-NHxe2x80x94;
(2,3,5-triCl-phenyl)-NHxe2x80x94; (2,4,5-triF-phenyl)-NHxe2x80x94; (2,6-diCl-3-Me-phenyl)-NHxe2x80x94; (3,5-diMe-4-MeO-phenyl)-NHxe2x80x94; (2-F-3-Cl-6-CF3-phenyl)-NHxe2x80x94;
benzyl-NHxe2x80x94; (3-quinolinyl)CH2NHxe2x80x94; (2-F-phenyl)CH2NHxe2x80x94; (2-Cl-phenyl)CH2NHxe2x80x94; (2-CF3-phenyl)CH2NHxe2x80x94; (2-CH3-phenyl)CH2NHxe2x80x94; (2-OMe-phenyl)CH2NHxe2x80x94; (2-CN-phenyl)CH2NHxe2x80x94; (2-OCF3-phenyl)CH2NHxe2x80x94; (2-SMe-phenyl)CH2NHxe2x80x94; (3-F-phenyl)CH2NHxe2x80x94; (3-Cl-phenyl)CH2NHxe2x80x94; (3-CF3-phenyl)CH2NHxe2x80x94; (3-CH3-phenyl)CH2NHxe2x80x94; (3-OMe-phenyl)CH2NHxe2x80x94; (3-CN-phenyl)CH2NHxe2x80x94; (3-OCF3-phenyl)CH2NHxe2x80x94; (3-SMe-phenyl)CH2NHxe2x80x94; (4-F-phenyl)CH2NHxe2x80x94; (4-Cl-phenyl)CH2NHxe2x80x94; (4-CF3-phenyl)CH2NHxe2x80x94; (4-CH3-phenyl)CH2NHxe2x80x94; (4-OMe-phenyl)CH2NHxe2x80x94; (4-CN-phenyl)CH2NHxe2x80x94; (4-OCF3-phenyl)CH2NHxe2x80x94;
(4-SMe-phenyl)CH2NHxe2x80x94; (2,3-diCl-phenyl)CH2NHxe2x80x94; (2,4-diCl-phenyl)CH2NHxe2x80x94; (2,5-diCl-phenyl)CH2NHxe2x80x94; (2,6-diCl-phenyl)CH2NHxe2x80x94; (3,4-diCl-phenyl)CH2NHxe2x80x94; (3,5-diCl-phenyl)CH2NHxe2x80x94; (2,3-diF-phenyl)CH2NHxe2x80x94; (2,4-diF-phenyl)CH2NHxe2x80x94; (2,5-diF-phenyl)CH2NHxe2x80x94; (2,6-diF-phenyl)CH2NHxe2x80x94; (3,4-diF-phenyl)CH2NHxe2x80x94; (3,5-diF-phenyl)CH2NHxe2x80x94; (2,3-diCH3-phenyl)CH2NHxe2x80x94; (2,4-diCH3-phenyl)CH2NHxe2x80x94; (2,5-diCH3-phenyl)CH2NHxe2x80x94; (2,6-diCH3-phenyl)CH2NHxe2x80x94; (3,4-diCH3-phenyl)CH2NHxe2x80x94; (3,5-diCH3-phenyl)CH2NHxe2x80x94; (2,3-diCF3-phenyl)CH2NHxe2x80x94; (2,4-diCF3-phenyl)CH2NHxe2x80x94; (2,5-diCF3-phenyl)CH2NHxe2x80x94; (2,6-diCF3-phenyl)CH2NHxe2x80x94; (3,4-diCF3-phenyl)CH2NHxe2x80x94; (3,5-diCF3-phenyl)CH2NHxe2x80x94; (2,3-diOMe-phenyl)CH2NHxe2x80x94; (2,4-diOMe-phenyl)CH2NHxe2x80x94; (2,5-diOMe-phenyl)CH2NHxe2x80x94; (2,6-diOMe-phenyl)CH2NHxe2x80x94; (3,4-diOMe-phenyl)CH2NHxe2x80x94; (3,5-diOMe-phenyl)CH2NHxe2x80x94; (2-F-3-Cl-phenyl)CH2NHxe2x80x94; (2-F-4-Cl-phenyl)CH2NHxe2x80x94; (2-F-5-Cl-phenyl)CH2NHxe2x80x94; (2-F-6-Cl-phenyl)CH2NHxe2x80x94; (2-F-3-CH3-phenyl)CH2NHxe2x80x94; (2-F-4-CH3-phenyl)CH2NHxe2x80x94; (2-F-5-CH3-phenyl)CH2NHxe2x80x94; (2-F-6-CH3-phenyl)CH2NHxe2x80x94; (2-F-3-CF3-phenyl)CH2NHxe2x80x94; (2-F-4-CF3-phenyl)CH2NHxe2x80x94; (2-F-5-CF3-phenyl)CH2NHxe2x80x94; (2-F-6-CF3-phenyl)CH2NHxe2x80x94; (2-F-3-OMe-phenyl)CH2NHxe2x80x94; (2-F-4-OMe-phenyl)CH2NHxe2x80x94; (2-F-5-OMe-phenyl)CH2NHxe2x80x94; (2-F-6-OMe-phenyl)CH2NHxe2x80x94; (2-Cl-3-F-phenyl)CH2NHxe2x80x94; (2-Cl-4-F-phenyl)CH2NHxe2x80x94; (2-Cl-5-F-phenyl)CH2NHxe2x80x94; (2-Cl-6-F-phenyl)CH2NHxe2x80x94; (2-Cl-3-CH3-phenyl)CH2NHxe2x80x94; (2-Cl-4-CH3-phenyl)CH2NHxe2x80x94; (2-Cl-5-CH3-phenyl)CH2NHxe2x80x94; (2-Cl-6-CH3-phenyl)CH2NHxe2x80x94; (2-Cl-3-CF3-phenyl)CH2NHxe2x80x94; (2-Cl-4-CF3-phenyl)CH2NHxe2x80x94; (2-Cl-5-CF3-phenyl)CH2NHxe2x80x94; (2-Cl-6-CF3-phenyl)CH2NHxe2x80x94; (2-Cl-3-OMe-phenyl)CH2NHxe2x80x94; (2-Cl-4-OMe-phenyl)CH2NHxe2x80x94; (2-Cl-5-OMe-phenyl)CH2NHxe2x80x94; (2-Cl-6-OMe-phenyl)CH2NHxe2x80x94; (2-CH3-3-F-phenyl)CH2NHxe2x80x94; (2-CH3-4-F-phenyl)CH2NHxe2x80x94; (2-CH3-5-F-phenyl)CH2NHxe2x80x94; (2-CH3-6-F-phenyl)CH2NHxe2x80x94; (2-CH3-3-Cl-phenyl)CH2NHxe2x80x94; (2-CH3-4-Cl-phenyl)CH2NHxe2x80x94; (2-CH3-5-Cl-phenyl)CH2NHxe2x80x94; (2-CH3-6-Cl-phenyl)CH2NHxe2x80x94; (2-CH3-3-CF3-phenyl)CH2NHxe2x80x94; (2-CH3-4-CF3-phenyl)CH2NHxe2x80x94; (2-CH3-5-CF3-phenyl)CH2NHxe2x80x94; (2-CH3-6-CF3-phenyl)CH2NHxe2x80x94; (2-CH3-3-OMe-phenyl)CH2NHxe2x80x94; (2-CH3-4-OMe-phenyl)CH2NHxe2x80x94; (2-CH3-5-OMe-phenyl)CH2NHxe2x80x94; (2-CH3-6-OMe-phenyl)CH2NHxe2x80x94; (2-CF3-3-F-phenyl)CH2NHxe2x80x94; (2-CF3-4-F-phenyl)CH2NHxe2x80x94; (2-CF3-5-F-phenyl)CH2NHxe2x80x94; (2-CF3-6-F-phenyl)CH2NHxe2x80x94; (2-CF3-3-Cl-phenyl)CH2NHxe2x80x94; (2-CF3-4-Cl-phenyl)CH2NHxe2x80x94; (2-CF3-5-Cl-phenyl)CH2NHxe2x80x94; (2-CF3-6-Cl-phenyl)CH2NHxe2x80x94; (2-CF3-3-CH3-phenyl)CH2NHxe2x80x94; (2-CF3-4-CH3-phenyl)CH2NHxe2x80x94; (2-CH3-5-CF3-phenyl)CH2NHxe2x80x94; (2-CF3-6-CH3-phenyl)CH2NHxe2x80x94; (2-CF3-3-OMe-phenyl)CH2NHxe2x80x94; (2-CF3-4-OMe-phenyl)CH2NHxe2x80x94; (2-CF3-5-OMe-phenyl)CH2NHxe2x80x94; (2-CF3-6-OMe-phenyl)CH2NHxe2x80x94; (2-OMe-3-F-phenyl)CH2NHxe2x80x94; (2-OMe-4-F-phenyl)CH2NHxe2x80x94; (2-OMe-5-F-phenyl)CH2NHxe2x80x94; (2-OMe-6-F-phenyl)CH2NHxe2x80x94; (2-OMe-3-Cl-phenyl)CH2NHxe2x80x94; (2-OMe-4-Cl-phenyl)CH2NHxe2x80x94; (2-OMe-5-Cl-phenyl)CH2NHxe2x80x94; (2-OMe-6-Cl-phenyl)CH2NHxe2x80x94; (2-OMe-4-CN-phenyl)CH2NHxe2x80x94; (2-OMe-4-CHO-phenyl)CH2NHxe2x80x94; (2-OMe-3-CH3-phenyl)CH2NHxe2x80x94; (2-OMe-4-CH3-phenyl)CH2NHxe2x80x94; (2-OMe-5-CH3-phenyl)CH2NHxe2x80x94; (2-OMe-6-CH3-phenyl)CH2NHxe2x80x94; (2-Oe-3-CF3-phenyl)CH2NHxe2x80x94; (2-OMe-4-CH3-phenyl)CH2NHxe2x80x94; (2-OMe-3-CF3-phenyl)CH2NHxe2x80x94; (2-OMe-6-CF3-phenyl)CH2NHxe2x80x94; (2-OMe-5-CF3-phenyl)CH2NHxe2x80x94; (2-acetyl-4-Me-phenyl)CH2NHxe2x80x94; (2-acetyl-4-MeO-phenyl)CH2NHxe2x80x94; (2-CH3CH(OH)-4-Cl-phenyl)CH2NHxe2x80x94; (2-CH3CH(OH)-4-Me-phenyl)CH2NHxe2x80x94; (2-CH3CH(OH)-4-MeO-phenyl)CH2NHxe2x80x94;
(3-CF3-4-Cl-phenyl)CH2NHxe2x80x94; (3-F-4-CHO-phenyl)CH2NHxe2x80x94; (3-CH3-4-CN-phenyl)CH2NHxe2x80x94; (3-CH3-4-MeO-phenyl)CH2NHxe2x80x94; (3-CH3-4-Cl-phenyl)CH2NHxe2x80x94; (3-CH3-4-F-phenyl)CH2NHxe2x80x94; (4F-3-CF3-phenyl)CH2NHxe2x80x94; (3-CH3-4-CO2Me-phenyl)CH2NHxe2x80x94; (3-CF3-4-C(O)CH3-phenyl)CH2NHxe2x80x94; (3-CHO-4-OMe-phenyl)CH2NHxe2x80x94;
(2,3,5-triCl-phenyl)CH2NHxe2x80x94; (2,4,5-triF-phenyl)CH2NHxe2x80x94; (2,6-diCl-3-Me-phenyl)CH2NHxe2x80x94; (3,5-diMe-4-MeO-phenyl)CH2NHxe2x80x94; and (2-F-3-Cl-6-CF3-phenyl)CH2NHxe2x80x94.
[9] In an another genus of each of the above embodiments, the present invention provides a novel compound of Formula (I) wherein X is a bond.
[10] In an another genus of each of the above embodiments, the present invention provides a novel compound of Formula (I) wherein X is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94.
[11] In an another genus of each of the above embodiments, the present invention provides a novel compound of Formula (I) wherein X is xe2x80x94OCH2xe2x80x94 or xe2x80x94SCH2xe2x80x94.
[12] In an another genus of each of the above embodiments, the present invention provides a novel compound of Formula (I) wherein X is xe2x80x94CH2xe2x80x94.
[13] In an another embodiment, the present invention provides a novel compound of Formula (I) wherein:
X is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x900)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, or xe2x80x94CH2NR10xe2x80x94;
R1 is selected from
C1-6 alkyl substituted with Z,
C2-6 alkenyl substituted with Z,
C2-6 alkynyl substituted with Z,
C3-6 cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;
C1-6 alkyl substituted with 0-2 R2,
C2-6 alkenyl substituted with 0-2 R2,
C2-6 alkynyl substituted with 0-2 R2,
aryl substituted with 0-2 R2, and
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O. and S, said heterocyclic ring system substituted with 0-2 R2;
Z is selected from H,
xe2x80x94CH(OH)R2,
xe2x80x94C(ethylenedioxy)R2,
xe2x80x94OR2,
xe2x80x94SR2,
xe2x80x94NR2R3 
xe2x80x94C(O)R2,
xe2x80x94C(O)NR2R3,
xe2x80x94NR3C(O)R2,
xe2x80x94C(O)OR2,
xe2x80x94OC(O)R2,
xe2x80x94CH(xe2x95x90NR4)NR2R3,
xe2x80x94NHC(xe2x95x90NR4)NR2R3,
xe2x80x94S(O)R21,
xe2x80x94S(O)2R2,
xe2x80x94S(O)2NR2R3, and xe2x80x94NR3S(O)2R2;
R2, at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
aryl substituted with 0-5 R42;
C3-10 carbocyclic residue substituted with 0-3 R41, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R3, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 alkoxy;
alternatively, R2 and R3 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R4)xe2x80x94;
R4, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R6a is H or C1-4 alkyl;
R6b is H;
alternatively, R6a and R6b are taken together to form xe2x95x90O or xe2x95x90S;
R7, R8, and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(0)2R12, S(O)NR12R3, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O) NHR15;
R10 is selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 alkoxy;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, C3-10 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, and NR14S(O)2R12;
R12, at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R14)xe2x80x94;
R14, at each occurrence, is independently selected from H and C1-4 alkyl;
R31, at each occurrence, is independently selected from
H, OH, halo, CF3, SO2R45, NR46R47, methyl, ethyl, and propyl;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47,
C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C3-5 cycloalkyl, C1-3 haloalkyl, C1-3 haloalkyl-oxy-, C1-3 alkyloxy-, C1-3 alkylthio-, C1-3 alkylxe2x80x94C(xe2x95x90O)xe2x80x94, and C1-3 alkyl-C(xe2x95x90O)NHxe2x80x94;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, xe2x95x90O,
C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R42, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, SR45, NR46R47, OR48, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R44, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R43 is C3-6 cycloalkyl or aryl substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H, halo, xe2x80x94OH, NR46R47, CO2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2, C1-4 alkyl, and C1-4 alkoxy;
R45 is C1-4 alkyl;
R46, at each occurrence, is independently selected from H and C1-4 alkyl;
R47, at each occurrence, is independently selected from H, C1-4 alkyl, xe2x80x94C(xe2x95x90O)NH(C1-4 alkyl), xe2x80x94SO2(C1-4 alkyl), xe2x80x94SO2(phenyl), xe2x80x94C(xe2x95x90O)O(C1-4 alkyl), xe2x80x94C(xe2x95x90O)(C1-4 alkyl) and xe2x80x94C(xe2x95x90O)H;
R48, at each occurrence, is independently selected from H, C1-4 alkyl, xe2x80x94C(xe2x95x90O)NH(C1-4 alkyl), xe2x80x94C(xe2x95x90O)O(C1-4 alkyl), xe2x80x94C(xe2x95x90O)(C1-4 alkyl), and xe2x80x94C(xe2x95x90O)H;
n is 1 or 2;
m is 1 or 2; and
n plus m is 2, 3, or 4;
provided when n is 1, m is 2, and R7, R8, and R9 are independently selected from H, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio or trifluoromethyl; then X is not a bond.
[14] In an another embodiment, the present invention provides a novel compound of Formula (I) wherein:
X is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, or xe2x80x94CH2Sxe2x80x94;
R1 is selected from
C2-5 alkyl substituted with Z,
C2-5 alkenyl substituted with Z,
C2-5 alkynyl substituted with Z,
C36 cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;
C1-5 alkyl substituted with 0-2 R2,
C2-5 alkenyl substituted with 0-2 R2, and
C2-5 alkynyl substituted with 0-2 R2;
Z is selected from H,
xe2x80x94CH(OH)R2,
xe2x80x94C(ethylenedioxy)R2,
xe2x80x94OR2,
xe2x80x94SR2,
xe2x80x94NR2R3,
xe2x80x94C(O)R2,
xe2x80x94C(O)NR2R3,
xe2x80x94NR3C(O)R2,
xe2x80x94C(O)OR2,
xe2x80x94OC(O)R2,
xe2x80x94CH(xe2x95x90NR4)NR2R3,
xe2x80x94NHC(xe2x95x90NR4)NR2R3,
xe2x80x94S(O)R2,
xe2x80x94S(O)2R2,
xe2x80x94S(O)2NR2R3, and xe2x80x94NR3S(O)2R2;
R2, at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
aryl substituted with 0-5 R42;
C3-10 carbocyclic residue substituted with 0-3 R41, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R3, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 alkoxy;
alternatively, R2 and R3 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R4)xe2x80x94;
R4, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R6a is H or C1-4 alkyl;
R6b is H;
alternatively, R6a and R6b are taken together to form xe2x95x90O or xe2x95x90S;
R7, R8, and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, (C1-4 haloalkyl)oxy,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)2NR12R13, NR14S(O)2R12, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94CN, xe2x80x94NO2,xe2x80x94NR46R47,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)2NR12R13, and NR14S(O)2R12;
R12, at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R14)xe2x80x94;
R14, at each occurrence, is independently selected from H and C1-4 alkyl;
R31, at each occurrence, is independently selected from
H, OH, halo, CF3, methyl, and ethyl;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, methyl, and ethyl;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, xe2x95x90O,
C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R42, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, SR45, NR46R47, OR48, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R44, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R43 is C3-6 cycloalkyl or aryl substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H, halo, xe2x80x94OH, NR46R47, CO2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2, C1-4 alkyl, and C1-4 alkoxy;
R45 is C1-4 alkyl;
R46, at each occurrence, is independently selected from H and C1-3 alkyl;
R47, at each occurrence, is independently selected from H, C1-4 alkyl, xe2x80x94C(xe2x95x90O)NH(C1-4 alkyl), xe2x80x94SO2(C1-4 alkyl), xe2x80x94SO2(phenyl), xe2x80x94C(xe2x95x90O)O(C1-4 alkyl), xe2x80x94C(xe2x95x90O)(C1-4 alkyl), and xe2x80x94C(xe2x95x90O)H;
R48, at each occurrence, is independently selected from H, C1-4 alkyl, xe2x80x94C(xe2x95x90O)NH(C1-4 alkyl), xe2x80x94C(xe2x95x90O)O(C1-4 alkyl), xe2x80x94C(xe2x95x90O)(C1-4 alkyl), and xe2x80x94C(xe2x95x90O)H;
n is 1 or 2;
m is 1 or 2; and
n plus m is 2, 3, or 4.
[15] In an another embodiment, the present invention provides a novel compound of Formula (I) wherein:
X is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
R1 is selected from
C2-4 alkyl substituted with Z,
C2-4 alkenyl substituted with Z,
C2-4 alkynyl substituted with Z,
C3-6 cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;
C2-4 alkyl substituted with 0-2 R2, and
C2-4 alkenyl substituted with 0-2 R2;
Z is selected from H,
xe2x80x94CH (OH) R2,
xe2x80x94C(ethylenedioxy)R2,
xe2x80x94OR2,
xe2x80x94SR2,
xe2x80x94NR2R3,
xe2x80x94C(O)R2,
xe2x80x94C(O)NR2R3,
xe2x80x94NR3C(O)R2,
xe2x80x94C(O)OR2,
xe2x80x94S(O)R2,
xe2x80x94S(O)2R2,
xe2x80x94S(O)2NR2R3, and xe2x80x94NR3S(O)2R2;
R2, at each occurrence, is independently selected from
phenyl substituted with 0-5 R42;
C3-10 carbocyclic residue substituted with 0-3 R41, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R3, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and
C1-4 alkoxy;
alternatively, R2 and R3 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R4)xe2x80x94;
R4, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R6a is H or C1-4 alkyl;
R6b is H;
alternatively, R6a and R6b are taken together to form xe2x95x90O or xe2x95x90S;
R7, R8, and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-3 haloalkyl)oxy, and
C1-4 alkyl substituted with 0-2 R11;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and (C1-3 haloalkyl)oxy;
R33, at each occurrence, is independently selected from
H, OH, halo, CF3, and methyl;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, xe2x95x90O,
C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R42, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, SR45, NR46R47, OR48, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R44, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R43 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl, each substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H, halo, xe2x80x94OH, NR46R47, CO2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;
R45 is methyl, ethyl, propyl, or butyl;
R46, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R47, at each occurrence, is independently selected from
H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, xe2x80x94C(xe2x95x90O)NH(methyl), xe2x80x94C(xe2x95x90O)NH(ethyl), xe2x80x94SO2(methyl), xe2x80x94SO2(ethyl), xe2x80x94SO2(phenyl), xe2x80x94C(xe2x95x90O)O(methyl), xe2x80x94C(xe2x95x90O)O(ethyl), xe2x80x94C(xe2x95x90O)(methyl), xe2x80x94C(xe2x95x90O)(ethyl), and xe2x80x94C(xe2x95x90O)H;
R48, at each occurrence, is independently selected from
H, methyl, ethyl, n-propyl, i-propyl, xe2x80x94C(xe2x95x90O)NH(methyl), xe2x80x94C(xe2x95x90O)NH(ethyl), xe2x80x94C(xe2x95x90O)O(methyl), xe2x80x94C(xe2x95x90O)O(ethyl), xe2x80x94C(xe2x95x90O)(methyl), xe2x80x94C(xe2x95x90O)(ethyl), and xe2x80x94C(xe2x95x90O) H;
n is 1 or 2;
m is 1 or 2; and
n plus m is 2 or 3.
[16] In an another embodiment, the present invention provides a novel compound of Formula (I) wherein:
X is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
R1 is selected from
ethyl substituted with Z,
propyl substituted with Z,
butyl substituted with Z,
propenyl substituted with Z,
butenyl substituted with Z,
ethyl substituted with R2,
propyl substituted with R2,
butyl substituted with R2,
propenyl substituted with R2, and
butenyl substituted with R2;
Z is selected from H,
xe2x80x94CH(OH)R2,
xe2x80x94OR2,
xe2x80x94NR2R3,
xe2x80x94C(O)R2,
xe2x80x94C(O)NR2R3,
xe2x80x94NR3C(O)R2,
xe2x80x94C(O)OR2,
xe2x80x94S(O)R2,
xe2x80x94S(O)2R2,
xe2x80x94S(O)2NR2R3, and xe2x80x94NR3S(O)2R2;
R2, at each occurrence, is independently selected from
phenyl substituted with 0-3 R42;
naphthyl substituted with 0-3 R42;
cyclopropyl substituted with 0-3 R41;
cyclobutyl substituted with 0-3 R41;
cyclopentyl substituted with 0-3 R41;
cyclohexyl substituted with 0-3 R41;
pyridyl substituted with 0-3 R41;
indolyl substituted with 0-3 R41;
indolinyl substituted with 0-3 R41;
benzimidazolyl substituted with 0-3 R41;
benzotriazolyl substituted with 0-3 R41;
benzothienyl substituted with 0-3 R41;
benzofuranyl substituted with 0-3 R41;
phthalimid-1-yl substituted with 0-3 R41;
inden-2-yl substituted with 0-3 R41;
2,3-dihydro-1H-inden-2-yl substituted with 0-3 R41;
indazolyl substituted with 0-3 R41;
tetrahydroquinolinyl substituted with 0-3 R41; and
tetrahydro-isoquinolinyl substituted with 0-3 R41;
R3, at each occurrence, is independently selected from
H, methyl, and ethyl;
R6a is H or C1-4 alkyl;
R6b is H;
alternatively, R6a and R6b are taken together to form xe2x95x90O or xe2x95x90S;
R7, R8, and R9, at each occurrence, are independently selected from H, F, Cl, methyl, ethyl, methoxy, xe2x80x94CF3, and xe2x80x94OCF3;
R41, at each occurrence, is independently selected from
H, F, Cl, Br, OH, CF3, NO2, CN, xe2x95x90O, methyl, ethyl, propyl, butyl, methoxy, and ethoxy;
R42, at each occurrence, is independently selected from
H, F, Cl, Br, OH, CF3, SO2R45, SR45, NR46R47, OR48 NO2, CN, xe2x95x90O, methyl, ethyl, propyl, butyl, methoxy, and ethoxy;
R45 is methyl, ethyl, propyl, or butyl;
R46, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R47, at each occurrence, is independently selected from
H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, xe2x80x94C(xe2x95x90O)NH(methyl), xe2x80x94C(xe2x95x90O)NH(ethyl), xe2x80x94SO2(methyl), xe2x80x94SO2(ethyl), xe2x80x94SO2(phenyl), xe2x80x94C(xe2x95x90O)O(methyl), xe2x80x94C(xe2x95x90O)O(ethyl), xe2x80x94C(xe2x95x90O)(methyl), xe2x80x94C(xe2x95x90O)(ethyl), and xe2x80x94C(xe2x95x90O)H;
R48, at each occurrence, is independently selected from
H, methyl, ethyl, n-propyl, i-propyl, xe2x80x94C(xe2x95x90O)NH(methyl), xe2x80x94C(xe2x95x90O)NH(ethyl), xe2x80x94C(xe2x95x90O)O(methyl), xe2x80x94C(xe2x95x90O)O(ethyl), xe2x80x94C(xe2x95x90O)(methyl), xe2x80x94C(xe2x95x90O)(ethyl), and xe2x80x94C(xe2x95x90O)H;
n is 1; and
m is 1.
[17] In an another embodiment, the present invention provides a novel compound of Formula (II): 
wherein:
b is a single bond wherein the bridging hydrogens are either cis or trans;
R1 is selected from
xe2x80x94(CH2)3C(xe2x95x90O)(4-fluoro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-bromo-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-methyl-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-methoxy-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-(3,4-dichloro-phenyl)phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(3-methyl-4-fluoro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2,3-dimethoxy-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-chloro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(3-methyl-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-t-butyl-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(3,4-difluoro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-methoxy-5-fluoro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-fluoro-1-naphthyl),
xe2x80x94(CH2)3C(xe2x95x90O)(benzyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-pyridyl),
xe2x80x94(CH2)3C(xe2x95x90O)(3-pyridyl),
xe2x80x94(CH2)3CH(OH)(4-fluoro-phenyl),
xe2x80x94(CH2)3CH(OH)(4-pyridyl),
xe2x80x94(CH2)3CH(OH)(2,3-dimethoxy-phenyl),
xe2x80x94(CH2)3S(3-fluoro-phenyl),
xe2x80x94(CH2)3S(4-fluoro-phenyl),
xe2x80x94(CH2)3S(xe2x95x90O)(4-fluoro-phenyl),
xe2x80x94(CH2)3SO2(3-fluoro-phenyl),
xe2x80x94(CH2)3SO2(4-fluoro-phenyl),
xe2x80x94(CH2)3O(4-fluoro-phenyl),
xe2x80x94(CH2)3O(phenyl),
xe2x80x94(CH2)3O(3-pyridyl),
xe2x80x94(CH2)3O(4-pyridyl),
xe2x80x94(CH2)3O(2-NH2-phenyl),
xe2x80x94(CH2)3O(2-NH2-5-F-phenyl),
xe2x80x94(CH2)3O(2-NH2-3-F-phenyl),
xe2x80x94(CH2)3O(2-NH2-4-F-phenyl),
xe2x80x94(CH2)3O(2-NH2-4-Cl-phenyl),
xe2x80x94(CH2)3O(2-NH2-4-OH-phenyl),
xe2x80x94(CH2)3O(2-NH2-4-Br-phenyl),
xe2x80x94(CH2)3O(2-NHC(xe2x95x90O)Me-4-F-phenyl),
xe2x80x94(CH2)3O(2-NHC(xe2x95x90O)Me-phenyl),
xe2x80x94(CH2)3NH(4-fluoro-phenyl),
xe2x80x94(CH2)3N(methyl)(4-fluoro-phenyl),
xe2x80x94(CH2)3CO2(ethyl),
xe2x80x94(CH2)3C(xe2x95x90O)N(methyl)(methoxy),
xe2x80x94(CH2)3C(xe2x95x90O)NH(4-fluoro-phenyl),
xe2x80x94(CH2)2NHC(xe2x95x90O)(phenyl),
xe2x80x94(CH2)2NMeC(xe2x95x90O)(phenyl),
xe2x80x94(CH2)2NHC(xe2x95x90O)(2-fluoro-phenyl),
xe2x80x94(CH2)2NMeC(xe2x95x90O)(2-fluoro-phenyl),
xe2x80x94(CH2)2NHC(xe2x95x90O)(4-fluoro-phenyl),
xe2x80x94(CH2)2NMeC(xe2x95x90O)(4-tluoro-phenyl),
xe2x80x94(CH2)2NHC(xe2x95x90O)(2,4-difluoro-phenyl),
xe2x80x94(CH2)2NMeC(xe2x95x90O)(2,4-difluoro-phenyl),
xe2x80x94(CH2)3(3-indolyl),
xe2x80x94(CH2)3(1-methyl-3-indolyl),
xe2x80x94(CH2)3(1-indolyl),
xe2x80x94(CH2)3(1-indolinyl),
xe2x80x94(CH2)3(1-benzimidazolyl),
xe2x80x94(CH2)3(1H-1,2,3-benzotriazol-1-yl),
xe2x80x94(CH2)3(1H-1,2,3-benzotriazol-2-yl),
xe2x80x94(CH2)2(H-1,2,3-benzotriazol-1-yl),
xe2x80x94(CH2)2(1H-1,2,3-benzotriazol-2-yl),
xe2x80x94(CH2)3(3,4 dihydro-1(2H)-quinolinyl),
xe2x80x94(CH2)2C(xe2x95x90O)(4-fluoro-phenyl),
xe2x80x94(CH2)2C(xe2x95x90O)NH(4-fluoro-phenyl),
xe2x80x94CH2CH2(3-indolyl),
xe2x80x94CH2CH2(1-phthalimidyl),
xe2x80x94(CH2)4C(xe2x95x90O)N(methyl)(methoxy),
xe2x80x94(CH2)4CO2(ethyl),
xe2x80x94(CH2)4C(xe2x95x90O)(phenyl),
xe2x80x94(CH2)4(cyclohexyl),
xe2x80x94(CH2)3CH(phenyl)2,
xe2x80x94CH2CH2CHxe2x95x90C(phenyl)2,
xe2x80x94CH2CH2CHxe2x95x90CMe(4-F-phenyl),
xe2x80x94(CH2)3CH(4-fluoro-phenyl)2,
xe2x80x94CH2CH2CHxe2x95x90C(4-fluoro-phenyl)2,
xe2x80x94(CH2)2(2,3-dihydro-1H-inden-2-yl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-5-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-3-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-4-Cl-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-4-OH-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-4-Br-phenyl),
xe2x80x94(CH2)3(1H-indazol-3-yl),
xe2x80x94(CH2)3(5-F-1H-indazol-3-yl),
xe2x80x94(CH2)3(7-F-1H-indazol-3-yl),
xe2x80x94(CH2)3(6xe2x80x94Cl-1H-indazol-3-yl),
xe2x80x94(CH2)3(6-Br-1H-indazol-3-yl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHMe-phenyl),
xe2x80x94(CH2)3(1-benzothien-3-yl),
xe2x80x94(CH2)3(6-F-1H-indol-1-yl),
xe2x80x94(CH2)3(5-F-1H-indol-1-yl),
xe2x80x94(CH2)3(6-F-2,3-dihydro-1H-indol-1-yl),
xe2x80x94(CH2)3(5-F-2,3-dihydro-1H-indol-1-yl),
xe2x80x94(CH2)3(6-F-1H-indol-3-yl),
xe2x80x94(CH2)3(5-F-1H-indol-3-yl),
xe2x80x94(CH2)3(5-F-1H-indol-3-yl),
xe2x80x94(CH2)3(9H-purin-9-yl),
xe2x80x94(CH2)3(7H-purin-7-yl),
xe2x80x94(CH2)3(6-F-1H-indazol-3-yl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHSO2Me-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHC(xe2x95x90O)Me-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHC(xe2x95x90O)Me-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHCO2Et-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHC(xe2x95x90O)NHEt-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHCHO-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2xe2x80x94OH-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-MeS-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHSO2Me-4-F-phenyl),
xe2x80x94(CH2)2C(Me)CO2Me,
xe2x80x94(CH2)2C(Me)CH(OH)(4-F-phenyl)2,
xe2x80x94(CH2)2C(Me)CH(OH)(4-Cl-phenyl)2,
xe2x80x94(CH2)2C(Me)C(xe2x95x90O)(4-F-phenyl),
xe2x80x94(CH2)2C(Me)C(xe2x95x90O)(2-MeO-4-F-phenyl),
xe2x80x94(CH2)2C (Me)C(xe2x95x90O)(3-Me-4-F-phenyl),
xe2x80x94(CH2)2C(Me)C(xe2x95x90O)(2-Me-phenyl),
xe2x80x94(CH2)2C(Me)C(xe2x95x90O)phenyl, 
R7, R8, and R9, at each occurrence, are independently selected from
hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenyl, benzyl,
HC(xe2x95x90O)xe2x80x94, methylC(xe2x95x90O)xe2x80x94, ethylC(xe2x95x90O)xe2x80x94, propylc(xe2x95x90O)xe2x80x94, isopropylC(xe2x95x90O)xe2x80x94, n-butylC(xe2x95x90O)xe2x80x94, isobutylC(xe2x95x90O)xe2x80x94, secbutylC(xe2x95x90O)xe2x80x94, tertbutylC(xe2x95x90O)xe2x80x94, phenylC(xe2x95x90O)xe2x80x94,
methylC(xe2x95x90O)NHxe2x80x94, ethylC(xe2x95x90O)NHxe2x80x94, propylC(xe2x95x90O)NHxe2x80x94, isopropylC(xe2x95x90O)NHxe2x80x94, n-butylC(xe2x95x90O)NHxe2x80x94, isobutylC(xe2x95x90O)NHxe2x80x94, secbutylC(xe2x95x90O)NHxe2x80x94, tertbutylC(xe2x95x90O)NHxe2x80x94, phenylC(xe2x95x90O)NHxe2x80x94,
methylamino-, ethylamino-, propylamino-, isopropylamino-, n-butylamino-, isobutylamino-, secbutylamino-, tertbutylamino-, phenylamino-,
provided that two of substituents R7, R8, and R9, are independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
In another subgenus of the above embodiments are compounds wherein b is a single bond wherein the bridge hydrogens are in a cis position; alternatively, are compounds wherein b is a single bond and the bridge hydrogens are in a trans position.
In another subgenus of the above embodiments are compounds wherein X is a bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, or xe2x80x94CH2xe2x80x94.
In another subgenus of the above embodiments are compounds wherein X is xe2x80x94Oxe2x80x94.
In another subgenus of the above embodiments are compounds wherein X is xe2x80x94OCH2xe2x80x94.
In another subgenus of the above embodiments are compounds wherein X is xe2x80x94Sxe2x80x94.
In another subgenus of the above embodiments are compounds wherein X is a bond.
In another subgenus of the above embodiments are compounds wherein X is xe2x80x94CH2xe2x80x94.
In another subgenus of the above embodiments are compounds wherein R6 and R6a is each H.
In another subgenus of the above embodiments are compounds wherein R7 and R9, at each occurrence, are independently selected from H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, and (C1-4 haloalkyl)oxy; alternatively R7 and R9, at each occurrence, are independently selected from H, F, Cl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, methyl, ethyl, vinyl, allyl, methoxy, and ethoxy; or, alternatively R7 and R9, at each occurrence, are independently selected from H, F, Cl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, methyl, and methoxy; or, alternatively R7 and R9, at each occurrence, are H.
In another subgenus of the above embodiments are compounds wherein R8 is methyl substituted by R11; phenyl substituted by 0-5 R33; xe2x80x94OR12; xe2x80x94SR12; or xe2x80x94NR12R13.
In another subgenus of the above embodiments are compounds wherein R8 is methyl substituted by R11.
In another subgenus of the above embodiments are compounds wherein R8 is phenyl substituted by 0-5 R33.
In another subgenus of the above embodiments are compounds wherein R8 is xe2x80x94NR12R13.
In another subgenus of the above embodiments are compounds wherein R8 is xe2x80x94OR12.
In another subgenus of the above embodiments are compounds wherein R8 is xe2x80x94SR12.
In another subgenus of the above embodiments are compounds wherein R1 is selected from H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl, xe2x80x94(Cl-3 alkyl)C3-6 cycloalkyl), xe2x80x94(C2-3 alkenyl)C3-6 cycloalkyl), and xe2x80x94(C2-3 alkynyl)C3-6 cycloalkyl.
In another subgenus of the above embodiments are compounds wherein R1 is selected from hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl, 2-hexyl, 2-ethylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-ethylpentyl, 3-methylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl; alternatively R1 is hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl, t-butyl, 2-propyl, 2-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl; or alternatively R1 is hydrogen, methyl, or ethyl.
In another subgenus of the above embodiments are compounds wherein m is 1 and n is 1 or 2; alternatively, are compounds wherein m is 1 and n is 1.
In an even further more preferred embodiment of the present invention, are compounds of Formula (I) selected from Table 1, Table 2, and Table 3.
In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
In a third embodiment, the present invention provides a method for the treatment a central nervous system disorder comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is a 5HT2a antagonist or a 5HT2c agonist.
In a preferred embodiment the compound is a 5HT2a antagonist.
In another preferred embodiment the compound is a 5HT2c agonist.
In a more preferred embodiment the present invention provides a method for the treatment central nervous system disorders including obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).
In a further preferred embodiment the central nervous system disorder comprises obesity.
In another further preferred embodiment the central nervous system disorder comprises schizophrenia.
In another further preferred embodiment the central nervous system disorder comprises depression.
In another further preferred embodiment the central nervous system disorder comprises anxiety.
In a fourth embodiment the present invention provides novel compounds of Formula (I) or pharmaceutically acceptable salt forms thereof for use in therapy.
In a fifth embodiment the present invention provides the use of novel compounds of Formula (I) or pharmaceutically acceptable salt forms thereof for the manufacture of a medicament for the treatment of central nervous system disorders including obesity, anxiety, depression, psychosis, schizophrenia, sleep.disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, and gastrointestinal disorders.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The numbering of the tetracyclic ring-system present in the compounds of Formula (I), as defined by nomenclature known to one skilled in the art, is shown for two examples in Formula (Ixe2x80x2), when k is 1 and n is 1; and in Formula (Ixe2x80x3), when k is 1 and n is 2: 
The tetracyclic ring-system present in compounds of Formula (I) occur as xe2x80x9ccisxe2x80x9d or xe2x80x9ctransxe2x80x9d isomers when the carbon-carbon bond b in Formula (I) is a single bond. As such, the terms xe2x80x9ccisxe2x80x9d and xe2x80x9ctransxe2x80x9d, in conjunction with the tetracyclic ring structure, refer to the configuration of hydrogen atoms on carbon atoms 8a and 11a in Formula (Ixe2x80x2) or, for example, on carbon atoms 9a and 12a in Formula (Ixe2x80x3), above. When both hydrogens are on the same side of the mean plane determined by the octahydro tetracyclic moiety then the configuration is designated xe2x80x9ccisxe2x80x9d, if not, the configuration is designated xe2x80x9ctransxe2x80x9d. It is understood that the above example is for demonstrative purposes only and not intended to limit the scope of the tetracyclic ring-system present in compounds of Formula (I). As such, it is understood that one skilled in the art of organic chemistry can apply the above numbering system to other values of m and n in the scope of compounds of Formula (I) to deterine the appropriate numbering. Additional Examples of the numbering of the tetracyclic ring-system are further provided below in the synthetic EXAMPLES. Lastly, it is understood that the use of xe2x80x9ccisxe2x80x9d or xe2x80x9ctransxe2x80x9d in the identification of the tetracyclic ring-system is not meant to construe the configuration of any other cis or trans geometric isomer in the molecule, for example, cis or trans butene.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g. R2, R11, R33, R41, R42 etc.) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R2, then said group may optionally be substituted with up to two R2 groups and R2 at each occurrence is selected independently from the definition of R2. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d, or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, xe2x80x9cC1-C6 alkylxe2x80x9d or xe2x80x9cC1-6 alkylxe2x80x9d denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.
xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration having the specified number of carbon atoms, for example xe2x80x9cC2-6 alkenylxe2x80x9d, and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration, having the specified number of carbon atoms, for example xe2x80x9cC2-6 alkynylxe2x80x9d, and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, having the specified number of carbon atoms. For example, xe2x80x9cC3-C6 cycloalkylxe2x80x9d denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
xe2x80x9cAlkoxylxe2x80x9d or xe2x80x9calkyloxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Similarly, xe2x80x9calkylthioxe2x80x9d is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulpher bridge.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluororo, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
As used herein, xe2x80x9ccarbocyclexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic ringxe2x80x9d or xe2x80x9cheterocyclic ring systemxe2x80x9d is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazolopyridinyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thiazolopyridinyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, IH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term xe2x80x9cbicyclic heterocyclic ring systemxe2x80x9d is intended to mean a stable 9- to 10-membered bicyclic heterocyclic ring formed from the substituent NR12R13, which is partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms, a nitrogen atom, and 1 or 2 additional heteroatoms independently selected from the group consisting of N, O and S. The additional nitrogen or sulfur heteroatoms may optionally be oxidized. The heterocyclic ring is attached to its pendant group by the nitrogen atom of the group NR12R13 and for which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. The term xe2x80x9cbicyclic heterocyclic ring systemxe2x80x9d is intended to be a subset of the term. xe2x80x9cheterocyclic ring systemxe2x80x9d. Preferred examples of a 9- to 10- membered bicyclic heterocyclic ring system are benzimidazolyl, benzimidazolinyl, benzoxazolinyl, dihydrobenzthiazolyl, dihydrodioxobenzthiazolyl, benzisoxazolinyl, 1H-indazolyl, indolyl, indolinyl, isoindolinyl, tetrahydro-isoquinolinyl, tetrahydro-quinolinyl, and benzotriazolyl.
Additionally, a subclass of preferred heterocycles are heterocycles which function as an isostere of a cyclic but non-heterocyclic substitutent such as xe2x80x94CH2xe2x80x94C(xe2x95x90O)-phenyl. Preferred examples of such heterocycles include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiophenyli benzoxazolyl, benzthiazolyl, benzisoxazolyl, furanyl, imidazolinyl, 1H-indazolyl, indolinyl, isoindolinyl, isoquinolinyl, oxazolyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, quinolinyl, thiazolyl, thiophenyl, and 1,2,3-triazolyl.
As used herein, the term xe2x80x9carylxe2x80x9d, or aromatic residue, is intended to mean an aromatic moiety containing six to ten carbon atoms, such as phenyl, pyridinyl and naphthyl.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula (I), and the like. xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
Throughout the details of the invention, the following abbreviations are used with the following meanings:
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction iconditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
The preparation of compounds of Formula (I) of the present invention may be carried out in a convergent or sequential synthetic manner. Detailed synthetic preparations of the compounds of Formula (I) are shown in the following reaction schemes. The skills required in preparation and purification of the compounds of Formula (I) and the intermediates leading to these compounds are known to those in the art. Purification procedures include, but are not limited to, normal or reverse phase chromatography, crystallization, and distillation.
Several methods for the preparation of the compounds of the present invention are illustrated in the schemes and examples shown below. The substitutions are as described and defined above.
The compounds of Formula (I) where n=1 and m=1 can be prepared as described in Scheme 1. Protection of the anilines (II) with BOC2O and a base such as triethylamine affords a carbamate intermediate which serves to direct subsequent deprotonation with sec-BuLi (TMEDA, xe2x88x9278xc2x0 C., ether) to occur at the adjacent aryl-H bond (see Beak, P., et. al., Tetrahedron Lett. 1989, 30, 1197; and Iwao, M., et. al., Heterocycles, 1992, 34, 1031). Quenching with an appropriate electrophile, such as N,N-dimethylformamide, affords the aldehydes (III). Horner-Emmons reaction of aldehydes (III) with an appropriate phosphonate (IV) in the presence of a base affords the xcex1, xcex2-unsaturated esters (V), where the olefin geometry can be controlled by the nature of the phosphonate (IV) and the conditions of the reaction. For example, under standard conditions, using a phosphonate (IV) where Rxe2x80x2 is Me or Et and using sodium hydride as a base leads to (V) with the E-olefin geometry as the nearly exclusive product. Alternatively, using a phosphonate (IV) where Rxe2x80x2 is 2,2,2-trifluoroethyl or Ar, generating its potassium enolate with potassium hexamethyldisilazide or potassium carbonate and 18-crown-6, and allowing it to react with aldehyde (III) leads to (V) with Z-olefin geometry as the nearly exclusive product (see Still, W. C., et. al., Tetrahedron Lett. 1983, 24, 4405; for a review of Z-selective Horner-Emmons reactions, see Jiro, M. Trends Org. Chem. 1998, 7, 63). Olefins (V) can serve as dipolarophiles in 1,3-dipolar cycloadditions with appropriate azomethine ylides to afford the pyrrolidines (VII) (for reviews of 1,3-dipolar cycloaddition chemistry of azomethine ylides, see 1,3-Dipolar Cycloaddition Chemistry, A. Padwa, Ed., Wiley-Interscience, New York, 1984). The required azomethine ylide can be generated in several ways, two preferred methods of which are described. The commercially available tertiary amine (VI) can be treated with 5-25 mol % TFA in methylene chloride to generate the required azomethine ylide and 1,3-dipolar cycloaddition then occurs at room temperature or reflux temperature to afford (VII). Alternatively, N-benzylglycine can be refluxed with paraformaldehyde in a suitable solvent such as toluene or benzene to generate the azomethine ylide. These methods produce (VII) where the pyrrolidine nitrogen is protected with a benzyl group. The 1,3-dipolar cycloaddition is stereospecific in that the stereochemistry of the olefin is retained and translated into the relative stereochemistry of the pyrrolidine II products. Thus, E-olefins undergo cyclization to produce pyrrolidines (VII) with a trans configuration of the 3,4-substituents on the pyrrolidine ring and Z-olefins undergo cyclization to produce pyrrolidines (VII) with a cis configuration of the 3,4-substituents on the pyrrolidine ring. Removal of the BOC group under acidic conditions, for example with TFA, affords an aniline which can undergo ring-closing condensation on the ester group, either with heating or with heating in the presence of an acid such as p-toluenesulfonic acid, to afford the tetracyclic compounds (VIII).
Compounds of Formula (I) where n=1 and m=1, and where R6a and R6b taken together are carbonyl, i.e. compounds (IX), are prepared by removal of the N-benzyl group of (VIII) either by catalytic hydrogenation over Pd/C or Pd(OH)2/C catalyst, or by reaction with xcex1-chloroethyl chloroformate (ACE-Cl) and subsequent refluxing in methanol, followed by N-alkylation of the secondary amine with an appropriate R1I and an appropriate base, such as potassium carbonate. Compounds of Formula (I) where n=1 and m=1, and where R6a and R6b are hydrogen, i.e. compounds (XI), can also be prepared from (VIII). Removal of the N-benzyl group as just described can be followed by protecting the secondary amine as a BOC carbamate by reaction with BOC2O to afford (X). Alternatively, (X) can be prepared directly from (VIII) by performing the catalytic hydrogenation using Pd(OH)2/C catalyst in the presence of BOC2O. Reduction of the lactam carbonyl with a reducing agent such as borane-tetrahydrofuran complex or DIBAL, followed by acidic BOC deprotection and subsequent N-alkylation as described above affords tetracyclic compounds (XI).
Alternatively, the compounds of Formula (I) where n 1 and m=1 and where the ring fusion is cis can be prepared as described in Scheme 2. The aldehydes (III), prepared as described in Scheme 1, can be condensed with dimethyl or diethyl malonate in the presence of catalytic piperidine or piperidine benzoate with removal of water to afford an xcex1,xcex2-unsaturated diester. Removal of the BOC group under acidic conditions and subsequent ring-closing condensation, which occurs spontaneously or with heating, affords the tricyclic compounds (XII). The 1,3-dipolar cycloaddition of this substrate with an appropriately generated azomethine ylide as described in Scheme 1 then affords the tetracyclic compounds (XIII) with a cis ring fusion. Decarboxylation can be accomplished by basic hydrolysis followed by heating the resulting acid, such as by refluxing in dioxane, or by heating the ester (XIII) under acidic conditions, to afford (XIV) which has retained the cis ring fusion. Tetracyclic compounds (XIV) can be converted to the compounds of Formula (I) where n=1 and m=1, where the ring fusion is cis, and where R6 and R6a taken together are carbonyl, i.e. compounds (XV), by the procedures described in Scheme 1. Likewise, compounds (XIV) can be converted to the compounds of Formula (I) where n=1 and m=1, where the ring fusion is cis, and where R6a and R6b are hydrogen, i.e. compounds (XVII), by the procedures described in Scheme 1. 
An alternative synthesis of the tricyclic esters (XII) is described in Scheme 3. Condensation of the anilines (II) with trimethyl or triethyl methanetricarboxylate at elevated temperature affords the tricyclic esters (XVIII). Conversion of the hydroxy group to chloro can be accomplished with phosphorous oxychloride and triethylamine at elevated temperature. The chloro can be reduced to afford compounds (XII) for example by treating with tributyltin hydride (see Neumann, W. P., Synthesis, 1987, 665). Compounds (XII) can then be carried on to the compounds of Formula (I) as described in Scheme 2. 
Compounds (XII) can be used as an alternative way to prepare compounds of Formula (I) where n=1 and m=1 as described in Scheme 4. Michael addition of nucleophiles such as cyanide ion or nitromethane anion to (XII) affords compounds (XIX). Reduction to a primary amine by catalytic hydrogenation, or, in the case of the nitromethane adduct, reducing agents such as tin (II) chloride, can be followed by ring-closing condensation under thermal conditions with or without acid catalysis to afford the tetracyclic bis-lactams (XX). Selective reduction of the less hindered secondary lactam can be accomplished with borane under controlled conditions, or by derivatization of the secondary lactam with phosphorous oxychloride or triethyloxonium tetrafluoroborate followed by reduction with sodium borohydride. N-alkylation of the resulting secondary amine as described in Scheme 1 affords compounds (IX). Alternately, (XX) can be exhaustively reduced using borane or LAH and subsequently N-alkylated as described to afford compounds (XI). 
Compounds (XII) can also be used as an alternative way to prepare compounds of Formula (I) where n=1 and m=1 and the ring fusion is cis, as described in Scheme 5. Chlorination of (XVIII) with phosphorous oxychloride provides a chloro analog which can be displaced by appropriate nucleophiles such as cyanide ion and nitromethane anion to afford (XXI). Catalytic hydrogenation and subsequent ring-closing condensation affords the cis-fused tetracyclic bis-lactam (XXII), the relative stereochemistry being set by the addition of hydrogen across the double bond. Following the procedures described in Scheme 4, bis-lactams (XXII) can be converted to cis-fused tetracyclic compounds (XV) and (XVII). 
The compounds of Formula (I) where n=1 and m=2 or where n=2 and m=1, and where the ring fusion is cis can be prepared as described in the following Schemes. As described in Scheme 6, (XII) can undergo [3+2] cycloaddition with 2-[(trimethylsilyl)methyl]-2-propen-1-yl acetate (XXIII) in the presence various palladium catalysts, such as (Ph3P)4Pd, (Ph3P)4Pd/dppe, Pd(OAc)2 and PPh3, or Pd(OAc)2 and P(OR)3, to afford a cyclopentane-fused compound containing an exo-methylene group (see Trost, B. M., et. al., J. Am. Chem. Soc. 1983, 105, 2315). Oxidative cleavage of the exo-methylene residue, such as with ozone or osmium tetroxide and sodium periodate, affords the tetracyclic cyclopentanones (XXIV) with a cis ring fusion. Decarboxylation can be accomplished as described previously by basic hydrolysis followed by heating, such as in refluxing dioxane, to afford (XXV). Ring expansion with incorporation of the nitrogen functionality can be accomplished in several ways. For example, Schmidt rearrangement (as described by Smith, P. A. S., J. Am. Chem. Soc., 1948, 320) is effected by treatment of the carbonyl derivative (XXV) with NaN3 and methanesulfonic acid to afford a mixture of the bicyclic lactams (XXVI) and (XXVII). Alternatively, this transformation may be carried out under Hoffmann rearrangement protocol (see, for example, Dike, S. Y., et. al., Bioorg. Med. Chem. Lett., 1991, 383), by initial formation of the oxime derivative of (XXV) by treatment with hydroxylamine hydrochloride. Subsequent rearrangement to the lactam is efficiently accomplished by heating in polyphosphoric acid to afford a mixture of the lactams (XXVI) and (XXVII). 
The conversion of lactams (XXVI) and (XXVII) to compounds of Formula (I) can be accomplished as described in Scheme 7. As described in Scheme 4, selective reduction of the secondary lactam of (XXVI) or (XXVII) followed by N-alkylation leads to tetracyclic compounds (XXVIII) or (XXX), respectively. Also as described in Scheme 4, exhaustive reduction of (XXVI) or (XXVII) and subsequent N-alkylation affords compounds (XXIX) or (XXXI), respectively.
Alternately, the compounds of Formula (I) where n=1 and m=2 or where n=2 and m=1, and where the ring fusion is trans can be prepared as described in Scheme 8. The E-olefin (XXXII), prepared as described in Scheme 1, can be subjected to the palladium catalyzed [3+2] cycloaddition with 2-[(trimethylsilyl)methyl]-2-propen-1-yl acetate (XXIII) as described in Scheme 6 and subsequently oxidatively cleaved to the ketone (XXXIII), where the E-olefin geometry is conserved in the product to give the trans cyclopentanone stereochemistry. Deprotection of the BOC carbamate under acidic conditions followed by ring-closing condensation under thermal conditions with or without acid catalysis affords the tetracyclic compounds (XXXIV). Ring expansion with incorporation of the nitrogen functionality can be accomplished in several ways as described in Scheme 6. For example, Schmidt rearrangement is effected by treatment of the carbonyl derivative (XXXIV) with NaN3 and methanesulfonic acid to afford a mixture of the bicyclic lactams (XXXV) and (XXXVI). Alternatively, this transformation may be carried out under Hoffmann rearrangement protocol by initial formation of the oxime derivative of (XXXIV) by treatment with hydroxylamine hydrochloride. Subsequent rearrangement to the lactam is efficiently accomplished by heating in polyphosphoric acid to afford a mixture of the lactams (XXXV) and (XXXVI). Following procedures described in previous schemes, (XXXV) and (XXXVI) can be converted to final compounds (XXXVII) and (XXXVIII), respectively, where depending on the lactam reduction conditions, R6a and R6b can be hydrogen or taken together to be a carbonyl residue. 
The anilines (II) which are used as starting materials for the compounds of Formula (I) are readily available by many methods known to those skilled in the art of organic synthesis. Also, many of the starting anilines (II) are commercially available, especially where R7, R8 and R9 are H, such as 1,2,3,4-tetrahydroquinoline (Xxe2x95x90CH2). Some methods which can be used to prepare anilines (II) are described in the following Schemes. In Scheme 9 are shown methods to prepare anilines (II) where X is O or S. The readily available ortho-amino phenols or thiophenols (XXXIX) can be O- or S-alkylated with a bromoacetate in the presence of a base such as sodium hydride or potassium carbonate. Subsequent heating affords the lactams (XL). Lactams (XL) can also be prepared by a similar sequence starting with the analogous ortho-nitro phenols or thiophenols and adding an additional nitro group reduction step after the O- or S-alkylation step. The lactams (XL) can be readily reduced by a variety of reducing agents, such as borane, LAH, DIBAL, etc., to afford the anilines (II) where X is O or S. Alternately, treatment of xcex1-halonitrobenzenes (XLI) with 2-hydroxy or 2-mercaptoacetates (XLII) in the presence of a suitable base such as triethylamine or potassium carbonate affords nitro esters (XLIII). Nitro group reduction by a variety of procedures, for example catalytic hydrogenation over palladium catalyst or treatment with tin (II) chloride, affords the aniline, which either spontaneously or upon heating provides the lactams (XL). Lactam reduction as described then affords the anilines (II) where X is O or S. 
To prepare anilines (II) where X is OCH2 or SCH2 very similar chemistry can be used as described in Scheme 10. The ortho-amino phenols or thiophenols (XXXIX) can be O- or S-alkylated with a bromopropionate (XLIV) in the presence of a base such as sodium hydride or potassium carbonate. Subsequent heating affords the seven-membered lactams (XLV). The lactams (XLV) can be readily reduced by a variety of reducing agents, such as borane, LAH, DIBAL, etc., to afford the anilines (II) where X is OCH2 or SCH2. Alternately, treatment of xcex1-halonitrobenzenes (XLI) with 3-hydroxy or 3-mercaptopropionates (XLVI) in the presence of a suitable base such as triethylamine or potassium carbonate affords nitro esters (XLVII). Nitro group reduction by a variety of procedures, for example catalytic hydrogenation over palladium catalyst or treatment with tin (II) chloride, affords the aniline, which either spontaneously or upon heating provides the lactams (XLV). Lactam reduction as described then affords the anilines (II) where X is OCH2 or SCH2. Alternatively, (XLI) can be displaced with alcohol or thiol (XLVIII) to afford (XLIX). Redcution of the nitro group followed by intramolecular N-alkylation, under the influence of basic and/or thermal conditions would afford anilines (II) where X is OCH2 or SCH2.
The anilines (II) where X is CH2O or CH2S can be prepared as described in Scheme 11. The ortho-amino benzyl alcohols and benzylthiols (L) are available by procedures known to those skilled in the art, for example, the benzyl alcohols are readily derived from reduction of appropriate anthranilic acid derivatives. O- or S-alkylation with bromoacetates in the presence of a base such as sodium hydride or potassium tert-butoxide affords an intermediate which when heated can undergo ring-closing condensation to afford the seven-membered lactams (LI). Reduction of the lactam as described previously affords anilines (II) where X is CH2O or CH2S. Alternatively, radical bromination of ortho-nitrotoluenes (LII) followed by displacement with a hydroxy- or mercaptoacetate (XLII) under basic conditions affords nitroesters (LIII). Nitro group reduction, ring-closing condensation and lactam reduction can be accomplished as described in previous Schemes to afford the anilines (II) where X is CH2O or CH2S. 
An alternative to the procedures described in Schemes 9-11 is described in Scheme 12. Esters (LIV) can be prepared by procedures known to those skilled in the art, including some of the procedures described in Schemes 9-11. Hydrolysis of the ester forms an acid which, when treated under Friedel-Crafts acylation conditions (see Ed. G. A. Olah, xe2x80x9cFriedel-Crafts and Related Reactionsxe2x80x9d , J. Wiley and Sons, New York, 1964, Vol 3, Pts 1 and 2 or Chem. Rev., 1955, 229, or Olah, G. A., xe2x80x9cFriedelxe2x80x94Crafts Chemistryxe2x80x9d, Wiley Interscience, New York, 1973, for varying conditions and protocols), i.e. strong Lewis acids (AlCl3, FeCl3, etc.), affords the cyclic ketones (LV). Incorporation of the nitrogen functionality can be accomplished in several ways. For example, Schmidt rearrangement (as described by Smith, P. A. S., J. Am. Chem. Soc., 1948, 320) is effected by treatment of the carbonyl derivative (LV) with NaN3 and methanesulfonic acid to afford the bicyclic lactam (LVI). Alternatively, this transformation may be carried out under Hoffmann rearrangement protocol (see, for example, Dike, S. Y., et. al., Bioorg. Med. Chem. Lett., 1991, 383), by initial formation of the oxime derivative of (LV) by treatment with hydroxylamine hydrochloride. Subsequent rearrangement to the lactam is efficiently accomplished by heating in polyphosphoric acid to afford the lactam (LVI). Reduction of the lactam (LVI) can be accomplished with a variety of reducing agents, for example, borane-THF complex, LAH and the like to afford the aniline intermediates (II). 
The preparation of anilines (II) where X is NR10, CH2NR10, NR10CH2, CONH or NHCO is shown in Scheme 13. N-Acylation of readily available ortho-nitroanilines (LVII) with chloroacetyl chloride (LVIII) in the presence of a suitable base, such as triethylamine, affords an amide. Nitro group reduction and ring closure under basic or thermal conditions affords the aniline (II) where X is NHCO. The ortho-nitroanilines (LIX), which can be derived from N-alkylation of (LVII) or by displacement of an ortho-fluoro- or ortho-chloro-nitrobenzene with R10NH2, can be N-acylated with (LX) where nxe2x80x3 is 1 or 2. Nitro group reduction and ring closure affords the amides (LXI). Reduction of the amide using borane or LAH then affords the anilines (II) where X is NR10CH2 or NR10. N-Alkylation of amino ester (LXIII) with a benzyl bromide (LXII) affords a benzylamine intermediate. Alternatively, this benzylamine can also be derived from reductive amination of an appropriate ortho-nitrobenzaldehyde with (LXIII) in the presence of acetic acid and a hydride source such as sodium cyanoborohydride or sodium triacetoxyborohydride. N-Alkylation with R10I and base or by a reductive amination procedure affords (LXIV). Nitro group reduction and ring closure affords an amide, which can be reduced with borane or LAH to give aniline (II) where X is CH2NR10. N-Acylation of amine (LXVI) with an acid chloride (LXV) in the presence of a base such as triethylamine affords amide (LXVII). Nitro group reduction and ring closure gives aniline (II) where X is CONH.
The preparation of compounds of Formula (I) with additional diversity of functionalization of the aromatic A ring of the tetracycle is shown in the following Schemes. As shown in Scheme 14, bromination of the compounds (LXVIII, R8xe2x95x90H) (where R6a and R6b of Formula (I) are H) when the amine is protected, for example, with the Boc or CBZ protecting groups, with, for example, NBS in DMF affords the R8 brominated derivatives (LXIX). These activated aryl derivatives (LXIX) act as excellent counterparts for a number of important synthetic transformations. 
For example, biaryl coupling is accomplished under Suzuki coupling protocol. For a review and leading references of palladium catalyzed cross coupling reactions, see Miyaura, N., Suzuki, A., Chem. Rev., 1995, 2457. One such procedure entails treatment of the aryl bromide (LXIX) with a functionalized aryl boronic acid (LXX) in the presence of a catalytic Pd(0) species, such as Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(OAc)2, Pd2(dba)3 and a suitable ligand such as PPh3, AsPh3, etc., or other such Pd(0) catalyst, and a base such as Na2CO3, Ba(OH)2 or Et3N in a suitable solvent such as DMF, toluene, THF, DME or the like, to afford the biaryl derivatives (LXXI). 
Alternatively formation of the boronic ester (i.e. (LXVIII, R8=B(OR)2) from the bromine derivative (LXIX) would allow for greater diversity in the subsequent coupling of this boronic acid with commercially available haloaromatic derivatives in a similar Suzuki coupling strategy as described above to afford compounds (LXXI). One such procedure is shown in Scheme 15. Treatment of bromides (LXIX) with a palladium catalyst such as Pd(PPh3)4 or Pd(PPh3)2Cl2 and a suitable base, a preferred one being potassium acetate, in the presence of diboron pinacol ester (LXXII) affords the aryl boronic ester (LXXIII). This boronic ester can undergo Suzuki coupling directly with a wide variety of commercially available aryl bromides (LXXIV) under typical Suzuki conditions as described in Scheme 13 to afford the biaryl compounds (LXXI). 
Similarly, biaryl coupling of the derivatives (LXXV) is shown in Scheme 16. Protection of the amine functionality must be carried out if R1=H (see Greene et.al for protections of amines). This is readily accomplished, for example, by treatment of the derivatives (LXXV) with (BOC)2O in aqueous sodium hydroxide and dioxane. Subsequent Suzuki coupling with a variety of aryl boronic acids is carried out as described above in Scheme 14, to afford the biaryl adducts (LXXVI). This protocol is amenable to R7, R8, and R9 bromide, iodide, triflates, and/or diazo derivatives (see Miyaura, N., Suzuki, A., Chem. Rev., 1995, 2457, for a review of aryl couplings). 
In addition, there exists a wide range of procedures and protocols for functionalizing haloaromatics, aryldiazonium and aryltriflate compounds. These procedures are well known by those in the art and described, for example, by Stanforth, S. P., Tetrahedron, 1998, 263; Buchwald, S. L., et. al., J. Am. Chem. Soc., 1998, 9722; Stille, J. K., et. al., J. Am. Chem. Soc., 1984, 7500. Among these procedures are biaryl couplings, alkylations, acylations, aminations, and amidations. The power of palladium catalyzed functionalization of aromatic cores has been explored in depth in the last decade. An excellent review of this field can be found in J. Tsuji, xe2x80x9cPalladium Reagents and Catalysts, Innovations in Organic Synthesisxe2x80x9d, J. Wiley and Sons, New York, 1995.
One such example is described in Scheme 17, where the aromatic A ring of Formula (I) is substituted with an arylamino group. Treatment of bromide (LXIX) with benzophenone imine in the presence of a palladium (0) catalyst, such as Pd2(dba)3, Pd(PPh3)4 or Pd(PPh3)2Cl2, and a suitable ligand such as BINAP or PPh3, and a base such as NaOtBu in a suitable solvent such as DMF, toluene, THF, DME or the like, affords an imine in which nitrogen is attached to the aromatic ring. Hydrolysis of this imine, for example with hydroxylamine and sodium acetate in methanol, affords the aniline (LXXVII). This aniline (LXXVII) can be treated with a wide variety of commercially available aryl bromides (LXXIV) in the presence of a palladium (0) catalyst, such as Pd2(dba)3, Pd(PPh3)4 or Pd(PPh3)2Cl2, and a suitable ligand such as BINAP or PPh3, and a base such as NaOtBu in a suitable solvent such as DMF, toluene, THF, DME or the like, to afford the biaryl anilines (LXXVIII). In analogy with Scheme 16, the chemistry described in Scheme 17 can also be applied to analogs of (LXIX) where the R7 or R9 groups are Br, I, OTf, etc., to afford analogs of (LXXVIII) where the arylamino group is on the R7 or R9 position. 
Another Example is shown in Scheme 18. Treatment of the anilines (LXXVII) with an appropriate benzaldehyde (LXXIX) in the presence of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride and generally under mildly acidic conditions, such as in the presence of acetic acid, in a suitable solvent such as 1,2-dichloroethane, THF, methanol or acetonitrile, affords the benzylamine analogs (LXXX). An alternate method for preparing benzylamines (LXXX) or xcex1-substituted benzylamines (LXXXII) proceeds from bromides (LXIX). Treatment of bromide (LXIX) with benzylamines (L), which can be chiral if R10 is an appropriate group, such as alkyl, in the presence of a palladium (0) catalyst, such as Pd2(dba)3, Pd(PPh3)4 or Pd(PPh3)2Cl2, and a suitable ligand such as BINAP or PPh3, and a base such as NaOtBu or Na2CO3 in a suitable solvent such as DMF, toluene, THF, DME or the like, affords the benzylamines (LXXXII). In analogy with previous schemes, the chemistry described in Scheme 18 can also be applied to analogs of (LXXVII) or (LXIX) where the R7 or R9 groups are NH2, Br, I, OTf, etc., to afford analogs of (LXXX) or (LXXXII) where the benzylamino group is on the R7 or R9 position. 
Another example is shown in Scheme 19. Treating bromides (LXIX) with an appropriate benzylic zinc reagent (LXXXIII), which can be generated from the corresponding benzyl halide, in the presence of a palladium (0) catalyst such as Pd(PPh3)4, Pd(PPh3)2Cl2, or Pd2(dba)3, and with or without a copper (I) salt, affords the derivatives (LXXXIV) where R8 is a benzyl group (see Knochel, P., et. al. Chem. Rev. 1993, 93, 2117; and Weichert, A., et. al. Syn. Lett. 1996, 473). This chemistry can also be extended to include a variety of alkylzinc and cycloalkylzinc reagents, which are available from the corresponding alkyl halides and cycloalkyl halides. In analogy with previous schemes the chemistry described in Scheme 19 can also be applied to analogs of (LXIX) where the R7 or R9 groups are Br, I, OTf, etc., to afford analogs of (LXXXIV) where the benzyl or alkyl or cycloalkyl group is on the R7 or R9 position. 
Another example is shown in Scheme 20. Compounds (LXIX), where X is bromo or preferably iodo, can be treated with various phenols (LXXXV) in the presence of a base such as Cs2CO3 and a copper catalyst such as CuPF6(CH3CN)4 at elevated temperature to afford biaryl ethers (LXXXVI) (see Sawyer, J. S. Tetrahedron 2000, 56, 5045). In analogy with previous schemes the chemistry described in Scheme 20 can also be applied to analogs of (LXIX) where the R7 or R9 groups are Br, I, OTf, etc., to afford analogs of (LXXXVI) where the aryloxy group is on the R7 or R9 position. 
The compounds of Formula (I) with substituted R1 sidechains can be prepared as described in Scheme 21. Alkylation of the derivatives (I, R1=H) with a haloalkyl ester, such as ClCH2(CH2)pCO2Me, in the presence of NaI or KI and a base such as K2CO3, Na2CO3 or the like, in dioxane or THF or other such solvent while heating (see Glennon, R. A., et. al., Med. Chem. Res., 1996, 197) affords the R1 alkylated esters. Subsequent formation of the activated amides (LXXXVII) is accomplished by treatment of the ester with N,O-dimethylhydroxylamine hydrochloride and a Lewis acid such as trimethylaluminum or triethylaluminum in toluene (see, for example, Golec, J. M. C., et. al., Tetrahedron, 1994, 809) at 0xc2x0 C. Treatment of the amide (LXXXVII) with a variety of organometallic agents, such as Grignard reagents R1aMgBr, alkyl and aryl lithium reagents etc. (see Sibi, M. P., et. al., Tetrahedron Lett., 1992, 1941; and more generally House, H. O., Modern Synthetic Reactions, W.A. Benjamin, Inc., Menlo Park, Calif., 1972), in a suitable solvent such as THF, ether, etc. at low temperatures affords the substituted ketones (LXXXVIII). 
Compounds of Formula (I) where R6a and R6a taken together are S can be prepared as described in Scheme 22. Compounds of Formula (I) where R6a and R6a taken together are O are treated with Lawesson""s reagent or P2S5 to afford the thiolactams (I), where R6a and R6a taken together are S. 
Compounds of Formula (I) where X is S(O)n, S(O)nCH2 and CH2S(O)n are prepared as shown in Scheme 23. Compounds of Formula (I) where X=S, SCH2 and CH2S can be readily oxidized by a variety of oxidizing agents, such as MCPBA, oxone or sodium periodate. Also, depending on the number of equivalents of oxidizing agent used, the reaction can be varied to provide compounds (I) where X is S(O)n, S(O)nCH2 and CH2S(O)n, where n=1 (sulfoxide) or n=2 (sulfone). 
The compounds of Formula (I) where R6a is C1-4 alkyl and R6b is H can be prepared as shown in Scheme 24. Treatment of (I), where R6a and R6b taken together are carbonyl, with an appropriate alkylcerium reagent, which is prepared in situ from the corresponding alkyllithium reagent, or an appropriate alkyl Grignard reagent, followed by reduction of the intermediate under acidic conditions with a borohydride reagent, such as sodium borohydride, affords the compounds (I), where R6a is C1-4 alkyl and R6b is H (see Nukui, S., et. al. J. Org. Chem. 1995, 60, 398; and Aube, J., et. al. Heterocycles 1993, 35, 1141). Alternatively, treatment of (I), where R6a and R6b taken together are carbonyl, with an appropriate dialkyl titanocene (see Petasis, N. A., et. al. Tetrahedron Lett. 1995, 36, 2393 and references cited therein) affords an amino olefin which can be reduced with sodium borohydride under acidic conditions to afford compounds (I), where R6a is C1-4 alkyl and R6b is H. 